Veterinary Parasitology 261 (2018) 27–52

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Veterinary Parasitology
journal homepage: www.elsevier.com/locate/vetpar

Review article

Anthelmintic drugs used in equine species T

a,⁎ b
Cengiz Gokbulut , Quintin A. McKellar
a
Department of Pharmacology, Faculty of Medicine, Balikesir University, Balikesir, Turkey
b
University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, United Kingdom

A R T I C LE I N FO A B S T R A C T

Keywords: Internal parasites of horses comprise an intractable problem conferring disease, production and performance
Anthelmintics losses. Parasitism can rarely be controlled in grazing horses by management alone and anthelmintic drugs have
Equines formed the basis of therapy and prophylaxis for the last sixty years. The pharmacology of the anthelmintic drugs
Horse available dictate their spectrum of activity and degree of efficacy, their optimal routes of administration and
Pony
characteristics which prevent some routes of administration, their safety tolerance and potential toxicities and as
Donkey
a consequence of their persistence in the body at effective concentrations their use in epidemiological control
Benzimidazoles
Macrocyclic lactones programmes. Their use has also resulted in the selection of parasites with genetically controlled characteristics
Endectocides which reduce their susceptibility to treatment, characteristics which are often common to whole chemical classes
Tetrahydropyrimidines of anthelmintics.
Resistance Pharmacological properties also confer compatibility in terms of safety and persistence with other anthel-
mintic drugs and thus the potential of combinations to treat parasites from different phylogenetic groups such as
nematodes, cestodes and trematodes and also the potential by agency of their different molecular mechanisms of
action to delay the selection of resistant genes. The major groups of anthelmintics now available, the benzi-
midazoles (BZD), macrocyclic lactones (MLs) and tetrahydropyrimidines are all highly effective against their
targeted parasites (primarily nematodes for BZD’s and ML’s and cestodes for tetrahydropyrimidines) easily
administered orally to horses and are well tolerated with wide margins of safety. Nevertheless, some parasitic
stages are inherently less susceptible such as hypobiotic stages of the small strongyles (cyathostomins) and for
some such as the adult stages of cyathostomins resistance has developed. Furthermore, for some less common
parasites such as the liver fluke unlicensed drugs such as the salicylanilide, closantel have been used.
A deep understanding of the pharmacology of anthelmintic drugs is essential to their optimal use in equine
species.

1. Anthelmintic drugs used in equine species
Modern anthelmintic drugs can be classified into seven distinct
classes according to their chemical structures and pharmacological
behaviours. Namely, benzimidazoles (BZDs), pro-benzimidazoles (pro-
BZDs), tetrahydropyrimidines (THPs), imidazothiazoles (IMTs), iso-
quinolines, salicylanilides (closantel) simple heterocycles, organopho-
sphates and macrocyclic lactones (MLs, avermectins and milbemycins
or endectocides) (Table 1). Each class of anthelmintics has a different
spectrum of activity and pharmacokinetic behaviour. The agents which
have a broad spectrum of anthelmintic activity can be classified into
three groups: Benzimidazoles and pro-BZDs, IMTs and THPs, and MLs.
Currently, these three classes of anthelmintic are licensed for use in
equine species against most important nematodes. The other anthel-
mintic compounds with narrow-spectrum of activity include piperazine
and compounds such as dichlorvos, trichlorvos, haloxan and closantel,
which are rarely used for the treatment of specific gastrointestinal
parasites or liver flukes. These anthelmintics are summarized in Tables
1 and 3 according to their chemical groupings and their efficacy, re-
spectively. Relatively limited data are available on internal parasites
and the pharmacology of anthelmintic drugs in donkeys and mules
compared to ruminants and horses because donkeys and mules have
been considered to be minor species and have been neglected in such
research. Most of the drugs in different classes used in horses and ru-
minants have been extrapolated for use in donkeys and mules without
optimization of dosing regimens or the determination of pharmacoki-
netic properties and have been used at the horse dose rate (Veneziano
et al., 2011). It has been reported that donkeys have a greater capacity
to metabolize certain drugs, compared to horses; thus, higher dosages
or shorter intervals could be required to maintain effective drug

⁎
Corresponding author.
E-mail address: cengizgokbulut@yahoo.com (C. Gokbulut).

https://doi.org/10.1016/j.vetpar.2018.08.002
Received 31 May 2018; Received in revised form 1 August 2018; Accepted 6 August 2018
0304-4017/ © 2018 Elsevier B.V. All rights reserved.
C. Gokbulut, Q.A. McKellar Veterinary Parasitology 261 (2018) 27–52

Table 1 provide effective control against nematodes with single or multiple

Anthelmintics available for treatment of helminth infections in equine species. drug resistance, and (2) to prevent or decelerate the development of
Class Route of Commonly Formulations resistance to each component of the anthelmintic combinations
administration recommended (not all licensed (Bartram et al., 2012). Other combinations of two or more distinct
dosage (mg/kg) for equines) classes of anthelminthic compounds with a different spectrum of ac-
tivity and different mechanisms of action are used to broaden the
Benzimidazoles
Cambendazole PO 20 Paste
spectrum of activity of the anthelmintic treatment, for instance to
Parbendazole PO 2.5 Powder, susp. control both nematodes and tapeworms in horses. Double combinations
Thiabendazole PO 50 Paste, susp., including ML + Praziquantel, BZ + Pyrantel or BZ + Piperazine are
powder commercially available in Australia, New Zealand, UK, Canada and
Mebendazole PO 8.8 Paste, granule
USA, and triple combinations of ML + BZ + Praziquantel or ML +
Fenbendazoleb PO 7.5 Paste, susp.,
granule Pyrantel + Praziquantel are commercially available in Australia and
Oxfendazole PO 10 Paste, pellet, New Zealand to control parasites in horses (Table 2).
susp. In the UK the BZ Fenbendazole, the ML’s Ivermectin and
Oxibendazole PO 10 Paste, susp.
Moxidectin, the THP Pyrantel and the Isoquinoline Praziquantel are
Albendazolea PO 5 Paste, susp.,
tablet
licensed for use in the horse. Nevertheless, a wide range of drugs are
Triclabendazolea PO 12 Tablet, susp. used in other licensing authorities, several are used off-label for specific
Pro-benzimidazoles parasitic conditions and some have been utilised experimentally in
Netobimina PO 10 Solution horses. Furthermore, characteristics of some anthelmintics common to
Febantel PO 6 Paste, susp.,
a group but not specific to horses or donkeys have been included in this
granule
Thiophanatea PO 50 Powder review because they add understanding to those used in the horse.
Tetrahydopyrimidines There are also a number of anthelmintics which have been used ex-
Pyrantel pamoateb PO 6.6 Paste, susp. tensively in horses in the past but are not currently used and these have
Pyrantel tartrate PO 6.6 Powder, pellet been included to provide comprehensive cover but also because they
Morantel PO 7.5-12.5 Paste
Imidazothiazole
have properties which might prove valuable for the future.
Levamisolea PO 10 Solution
Salicylanilides 2. Benzimidazoles and Pro-benzimidazoles
Closantela PO 10-20 Solution
Isoquinoline
The Benzimidazoles (BDZs) were the first safe and effective broad-
Praziquantelb PO 1.0 Paste/oral gel
Simple heterocycles spectrum anthelmintics which were used widely in the treatment of a
Phenothiazine PO 75 Powder variety of gastrointestinal parasitic infections in veterinary and human
Piperazine PO 200 Powder medicine. The BZD and pro-BZDs are a large family of compounds that
Organophosphates are related to thiabendazole (TBZ) which was first released for use in
Dichlorvos PO 20 Paste, pellet
Haloxon PO 60 Paste, powder
horses as an anthelmintic in 1961 (Drudge et al., 1981). These drugs
Trichlorfon PO 40 Paste, powder have common features such as broad-spectrum anthelmintic activity
Macrocyclic lactones and relatively low mammalian toxicity. Benzimidazole anthelmintics
Avermectins licensed internationally for use in horses for the treatment of gastro-
Ivermectinb PO, Ta 0.2-0.5 Paste, drench,
intestinal helminthiases and for lungworm and migrating strongyle
tablet
Abamectin PO 0.2 Paste, oral gel infections, include TBZ, mebendazole (MBZ) oxibendazole (OXB) fen-
Doramectin PO 0.2 Oral gel bendazole (FBZ), oxfendazole (FBZSO), cambendazole (CBZ) and the
Eprinomectina T 0.5 Solution pro-BZD, febantel (FBT).
Milbemycins All BZDs have poor water solubility; consequently, the development
Moxidectinb PO 0.2-0.4 Oral gel
of formulations for parenteral administrations has been limited. For this
PO: per os; T: Topical; susp.: Suspension. reason, they are primarily administered as oral pharmaceutical forms
a
Not licensed use for horse. such as drenches, tablets, bolus, paste or feed additives. Only rico-
b
Contained in products licensed for use in horses in the UK. bendazole (the sulphoxide metabolite of ABZ) has been available as an
injectable formulation and licensed for use in ruminant species.
concentrations in donkeys (Matthews et al., 1997; Grosenbaugh et al.,
2011). 2.1. Chemistry and metabolism
In equine species, anthelmintics may be given orally or by the na-
sogastric route for treatment of gastrointestinal parasitic infections. A According to their chemical structure, the BZD and pro-BZD an-
wide variety of formulations are available, including drenches, gels, thelmintics can be classified into four groups (Lanusse and Prichard,
pastes, granules, and powders for feed additives. Parenteral adminis- 1993).
tration of anthelmintics including endectocides is not utilised in equine
species. After parenteral administration, rare adverse reactions such as 1 BZD thiazolyl, including thiabendazole (TBZ) and cambendazole
Clostridium spp. infections and anaphylaxis have been observed and (CBZ);
these undesirable effects were responsible for the withdrawal of the 2 BZD methylcarbamates, including OXB, FBZ and OFZ or FBZSO,
parenteral preparation of IVM for use in the horse in 1984 (Campbell MBZ, albendazole (ABZ), albendazole sulphoxide (ABZSO) or rico-
et al., 1989). bendazole (RBZ), parbendazole (PBZ), flubendazole (FLBZ), luxa-
Anthelmintic drug combinations are increasingly used to control bendazole (LXB);
parasites in domestic animals including equine species. Dual or triple 3 Halogenated BZD thiols, of which triclabendazole (TCBZ) is the only
combinations of anthelminthic compounds with a similar spectrum of one currently available,
activity and different mechanisms of action are widely used in various 4 Pro-Benzimidazoles, including febantel (FBT), thiophanate (TPT)
parts of the world for the control of horse parasites (summarized in and netobimin (NTB).
Table 2). Such combinations are made for two main purposes: (1) to
A 1,2-diaminobenzene ring forms the central ring structure of all the

28
C. Gokbulut, Q.A. McKellar
Table 2
The anthelmintic combinations commercially available for the treatment of helminth infections in equine species.
Combinations
Double combinations
OFZ (20%) / PYR (26%)
OFZ (17.5%) / Morantel (24.5%)
OFZ (10.72%) / Piperazine (21.44%)
IVM (1.87%) / Praziquantel (14.3%)
ABM (0.4%) / Morantel (16.7%)
ABM (0.37%) / Praziquantel (4.62%)
MXD (2.0%) / Praziquantel (12.5%)
DRM (1.78%) / Praziquantel (22.29%)
Triple combinations
IVM (0.4%) / FBZ (20%) / Praziquantel (5.0%)
IVM (0.6%) / PYR (39%) / Praziquantel (4.3%)
MXD (0.8%) / OFZ (20%) / Praziquantel (5.0%)
ABM (0.4%) / OFZ (20%) / Praziquantel (5.0%)
BZD anthelmintics. The difference between each agent is associated
with different substitutions at the 2 and 5 substitute positions of the
central ring structure (Fig. 1). The pro-drugs enter the host body where
they are metabolised into the active BZD compounds by the gastro-
intestinal microflora and liver. Febantel is metabolised into FBZ, TPT
into LXB and NTB into ABZ. The chemical structures of BZD and pro-
BZD anthelmintics and metabolic pathways of FBZ, OFZ, ABZ and TCBZ
are shown in Figs. 1 and 2, respectively.
Although xenobiotic metabolism occurs mainly in the liver, extra-
hepatic tissues including plasma, kidney, lungs and gastrointestinal
tract and microflora are also involved. Biotransformation of drugs
generally results in metabolites of the parent drug which have reduced
or no activity (Baggot, 1974). Benzimidazoles and pro-BZDs are ex-
tensively metabolised in all animal species and biotransformation of
BZDs generally results in metabolites of the parent drug which have
reduced or no activity although the less oxidised sulphide metabolites
of FBZSO (FBZ) and ABZSO (ABZ) are thought to be active and the BZD
metabolites of the pro-BZD’s are the active moieties. The plasma
elimination half-lives of the parent drugs are short, and the metabolic
moieties predominate in plasma and tissues and in excreta of the host as
well as in parasites recovered from BZD-treated animals (Delatour and
Parish, 1986). Albendazole, FBZ, TCBZ and the pro-BZs (FBT and NTB),
which are commercially available thioether and sulphide BZs com-
monly undergo a sulphoxidation by gastrointestinal microflora and
liver microsomes. They are reversibly metabolised to their sulphoxide
derivatives (Marriner and Bogan, 1981b). Irreversible sulphonation
follows sulphoxidation and is a slower oxidative step resulting in a
sulphone metabolite (Averkin et al., 1975).
Hydroxylation is another important metabolic pathway of the BZDs.
In sheep, it was demonstrated that hydroxy OFZ (OH-FBZSO) and hy-
droxy FBZ (OH-FBZ) were major hepatic metabolites of FBZ, after in-
traruminal administration (Hennessy et al., 1993). These metabolites
are excreted directly into the bile as free or conjugated metabolites
(Hennessy et al., 1993). Lacey et al. (1987) reported that OH-FBZ was
intrinsically more active than the parent FBZ in vitro in binding to
parasite tubulin. Mebendazole and FLBZ undergo carbonyl reduction to
the corresponding alcohol (Vandenbossche et al., 1982). The alcohol
metabolite of MBZ was found at higher concentrations than the parent
drug in sheep plasma (Behm et al., 1983). However, MBZ metabolites
are not thought to have an anthelmintic activity (Meuldermans et al.,
1976).
The pharmacokinetics and activity of BZD anthelmintics are parti-
cularly influenced by the physicochemical properties and metabolic
pathways of the active molecules. These compounds are only sparingly
soluble in water and the absorption and pharmacokinetics of these
drugs are affected by their aqueous solubility (Ngomuo et al., 1984).
Pro-BZD compounds are relatively much more soluble in water com-
pared to other BZDs; and this provides an advantage to create different
29
Veterinary Parasitology 261 (2018) 27–52
Route of administration Formulations
PO Paste/oral gel, tablet
PO Paste
PO Paste/oral gel
PO Paste, tablet
PO Paste
PO Paste
PO Oral gel
PO Paste
PO Paste
PO Paste
PO Paste
PO Paste
PO Paste
pharmaceutical formulations and better absorption from the gastro-
intestinal tract of hosts following oral administration. Febantel and NTB
are commercially available pro-BZD drugs. Their anthelmintic activity
is due to the fact that they are metabolised in the animal to form the
biologically active BZD carbamate nucleus. Febantel is a phenylguani-
dine that is hydrolysed and then cyclized to the active metabolite FBZ
(Delatour et al., 1982). Netobimin is a nitrophenylguinidine which
undergoes both reduction and cyclization to form the active compound
ABZ (McDougall et al., 1985).
2.2. Efficacy and spectra of activity
The anthelmintic activities of BZDs and pro-BZDs against common
gastrointestinal parasites in equine species are shown in Table 3. BZD
and pro-BZD drugs are used widely to treat gastrointestinal hel-
minthiasis including migrating strongyle larvae and lungworm infec-
tions (Marriner and Bogan, 1985). Most of the BZDs (CBZ, OFZ, FBZ,
MBZ and OXB) and the pro-BZD (FBT) are highly effective (above 90%)
against adult forms of the large strongyles, cyathostomins, mature
Oxyuris equi, the small pinworm (Probstmayria vivipara) and Trichos-
trongylus axei in horses (Courtney and Robertson,1997).
There are some notable differences in the efficacy of BZDs against
different parasite species. Thiabendazole needs to be given at a higher
dosage for Parascaris equorum and TBZ, FBZSO and FBZ are only ef-
fective against Strongyloides westeri when given at a higher dose. At
7.5 mg/kg daily for five days, FBZ was shown to have 94.6% efficacy
against larval stages of cyathostomins in enteric mucosa; to be 80%
effective against migrating larvae of Strongylus vulgaris and fully effec-
tive against migrating stages of Strongylus edentatus (Duncan et al.,
1980). It has been shown that FBZ was highly efficacious against P.
equorum (faecal egg count reduction range: 97.5–99.9%), however, ef-
ficacy of FBZ was low against Strongylus spp (faecal egg count reduction
range: 0.4–41%) at a dose of 7.5 mg/kg following oral administration in
horses in the UK because of the development of BZD resistance (Relf
et al., 2014).
Oxibendazole has little or no effect against migrating stages of S.
vulgaris, T. axei, Habronema muscae and Drashia megastoma (Kates et al.,
1975; Nawalinski and Theodorides, 1977) in horses and ponies. Al-
though, Parbendazole has not been approved for horses, it is fully ef-
fective against migrating larvae of S. edentatus at 20 mg/kg BW, (Lyons
et al., 1980), but ineffective against 7-day-old larvae of S. vulgaris
(Drudge and Lyons, 1970). Parbendazole has no activity against T. axei,
Habronema spp. D. megastoma and S. westeri (Lyons et al., 1980). Al-
bendazole is effective against fourth-stage larvae of S. vulgaris with
minor signs of toxicity at a dosage rate of 50 mg/kg twice a day for 2
days (Georgi et al., 1980).
Although NTB is not licensed for use in any equine species, NTB
treatment resulted in a high reduction of patent strongyle infections in
C. Gokbulut, Q.A. McKellar Veterinary Parasitology 261 (2018) 27–52

Fig. 1. Chemical structures of benzimidazole (BZ) and pro-benzimidazole (pro-BZD) anthelmintics.

horses at a dose of 10 mg/kg BW (Gokbulut et al., 2009). Thus, NTB cent 2 and 4 weeks, respectively after treatments in horses.
reduced the strongyle EPG by 100% for 4 weeks. This is in line with the Most common endoparasites that affect horses can also cause
earlier report of (Mirck and Vanmeurs, 1982), who indicated that orally parasitic infections in donkeys and generally, the anthelmintic drugs
administered ABZ reduced the faecal egg counts by 99.1 and 93.9 per licensed for use in horses are effective in donkeys. The anthelmintic

30
C. Gokbulut, Q.A. McKellar
Fig. 2. Metabolic pathways of fenbendazole (FBZ)\ oxfendazole (OFZ or FBZSO), albendazole (ABZ) and triclabendazole (TCBZ).
drugs with broad spectrum of activity including BZDs available for use
in horses have been shown to be effective against the common helminth
infections in donkeys at doses determined for horses (Malan and
Reinecke, 1979; Taylor and Craig, 1993; Trawford and Tremlett, 1996;
Imam et al., 2010; Gokbulut et al., 2014). However, in donkeys, after
oral administration of FBZ at a dose of 50 mg/kg BW, neither the parent
molecule or it’s metabolites were detected in blood and this may cause
the lack of efficacy against lungworm (Dictyocaulus arnfieldi) infection
(Taylor and Craig, 1993). Mebendazole, FBZ and OFZ are registered
BZD compounds for use in donkeys. They have similar spectra of ac-
tivity in this species as in the horse. However, for treatment of D.
arnfieldi in the donkey, higher dose of MBZ should be used (20 mg/kg)
and administered on 5 consecutive days (McKellar and Scott, 1990).
Recently, it has been shown that in donkeys, MBZ paste at a horse
dosage (10 mg/kg BW) was effective (> 95% efficacy) and safe for the
treatment of cyathostomins in donkeys (Gokbulut et al., 2016a). Tri-
clabendazole, at 12 mg/kg BW is effective against Fasciola hepatica in-
fection in donkeys following oral administration (Trawford and
Tremlett, 1996).
2.3. Mode of action
Benzimidazoles and pro-BZDs are considered to have a similar mode
of action. Differences in their efficacy largely reflect differences in
bioavailability. The mode of action of BZD anthelmintics was initially
thought to be inhibition of various parasite metabolic enzymes in-
cluding fumarate reductase and malate dehydrogenase (Tejada et al.,
1987). However, it is now established that BZD anthelmintic com-
pounds prevent polymerisation of the microtubules in eukaryotic cells
by selectively binding to parasite β-tubulin resulting in the destruction
of cell structure and consequent death of the parasite (Lacey, 1990;
Martin, 1997). Borgers et al. (1975) reported that after exposure of cells
from nematodes to MBZ, the cytoplasmic microtubules disappeared,
and this caused disruption in the migration of subcellular organelles
with a failure of transport of secretory materials in the cells. Prolonged
storage of the secretory granules caused lysis of the cell cytoplasm and
31
Veterinary Parasitology 261 (2018) 27–52
disintegration of the cells. It was found that the BZDs competed for the
attachment site on β-tubulin with colchicine, a substance known to
prevent cell division in the metaphase (Sangster et al., 1985; Lacey and
Gill, 1994).
The selective anthelmintic action of BZDs is due to differences in the
sensitivity of host and parasite cells to the tubulin binding effects of
these drugs (Friedman and Platzer, 1980). Benzimidazoles bind re-
versibly to mammalian tubulin, whereas they bind irreversibly to ne-
matode tubulin (Lacey and Gill, 1994) and thus prevent permanent
tubulin polymerisation to microtubules in Nematodes. In addition, the
selective toxicity may be due to differences between the structure of
host and nematode microtubules. Mammalian cells have 13 micro-
tubule protofilaments whereas nematode cells have 11, 12 and 14
protofilaments (Chalfie and Thomson, 1979).
2.4. Safety and toxicity
The BZD and pro-BZ anthelmintics have a high therapeutic index
and are extremely well tolerated by mammals. BZD compounds with
low-solubility may be relatively less toxic than the more water-soluble
compounds because insufficient drug is absorbed to exert a systemic
toxic effect (McKellar and Scott, 1990).
In horses, including pregnant mares, FBZ at a dose of 100 mg/kg
produced no adverse effects (Becker, 1975) and reproductive function
of stallions was not affected (Squires et al., 1978). In sheep FBZ is
generally safe at high doses but when FBZ was given at 45 mg/kg daily
for 30 days, myocardial lesions and vacuolation of the liver par-
enchyma were observed (Booze and Oehme, 1982), and although no
such chronic toxicity studies have been carried out in the horse one
might expect similar organ and tissue susceptibility.
The main toxic effect of BZDs is teratogenicity. This varies with the
structure of the BZD compounds and the animal species (Delatour and
Parish, 1986). The teratogenic activity of FBZSO and ABZSO has been
shown when administered to rats in early pregnancy (Delatour et al.,
1984). Sheep and rats are much more sensitive than other species of
animals to the teratogenic activity of the BZDs and extensive studies
C. Gokbulut, Q.A. McKellar Veterinary Parasitology 261 (2018) 27–52

+++, 95–100% efficacy; ++, 80–100% efficacy; +, 0–100 efficacy; o, no efficacy; -, insufficient data. * MXD exhibited moderate efficacy (64% and 85%) against early third stage (EL3) and late third stage (LL3)/fourth
have been carried out in these species. Congenital malformations were
Trichostrongylus axei
reported during early gestation in ewes following administration of CBZ
(Delatour et al., 1976), FBZSO (Delatour et al., 1977) ABZ (Johns and
Philip, 1977) and FBT (Chement, 1982). The main congenital defects

+++

+++

+++
+++
identified in the lambs were skeletal malformations, occurring mainly

++
+
in the long bones, pelvis, joints and digits. The microtubular activity of
o
o
o

o
o

o
–
–

–
–

–
BZD compounds may lead to their teratogenic activity (McKellar and
megastoma

Scott, 1990). It is the unbound drug or metabolites, which are likely to

Draschia

exert toxic effects in mammals and the tightly protein-bound residues

that persist in the tissues for longer periods of time, are thought to be of
o
o
o
o
o
o

o
–

–
–

–
–
–
–
–

–
–
lower significance toxicologically (Delatour and Parish, 1986).
Habronema spp.

Teratogenic activity studies of the BZDs in early pregnancy in rats

stage (L4) encysted cyathostomins, respectively (Reinemeyer et al., 2015) whereas IVM was ineffective (0%) against LL3 and L4 stages of cyathostomin larvae (Xiao et al., 1994).
have shown that this species has similar sensitivity to sheep.
Teratogenic and embryo lethal effects have been reported for PBZ,

++
++
MBZ, CBZ, ciclobendazole, carbendazim, FBZSO, ABZ, FBT and NTB
o
o
o
o
o

o
o
o

o
–
–

–
–
(Delatour and Parish, 1986; Tsuchiya et al., 1987; Mantovani et al.,
Strongyloides

1995; El-Makawy et al., 2006). In male rats, testicular degeneration and

abnormal spermatogenesis were produced by high doses of carben-
+++
+++

+++

+++

+++
+++
westeri

dazim (Styles and Garner, 1974) and the mutagenic effects of carben-
o
o
o
o

o
o
–

–
–
–

–
–

dazim have also been shown in other species at high doses (Seiler,
equorum L5

1976).
Parascaris

+++

+++
+++
+++
+++
+++
+++

+++
+++
+++
+++
+++
+++
The activity of anthelmintic compounds used for the treatment of common gastrointestinal nematodes in equines (Adapted from Mirck, 1985).

++
++

2.5. Pharmacokinetics
+

+
–
equorum L4

The active BZD anthelmintics are thought to have a similar mode of

Parascaris

action (Coles, 1977). The different efficacies of the BZDs in vivo have
+++
+++
+++

+++
+++
+++

+++
+++

therefore been attributed largely to different pharmacokinetics within

–
–
–
–
–
–
–
–

the host (Bogan, 1983) and in vitro, to different solubility and therefore
absorption of the drug from culture media by the test parasites (Scott,
Strongylus
vulgaris

1988). Anthelmintic activity depends on the duration of parasite ex-

+++
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++

+++
+++
+++
+++

posure to effective concentrations of the active compound (Baggot and

+
+
–

McKellar, 1994), thus observations on the pharmacokinetics of BZDs

are extremely important.
Strongylus
edentatus

Most of the BZD anthelmintics including methylcarbamate BZDs

+++
+++
+++

+++
+++
+++
+++
+++

+++
+++
++

++

have very limited absolute solubility in water and the dispositions of

+
+
+
o

o
–

these drugs are affected by their aqueous solubility. The relatively rapid
dissolution and consequent absorption from the gastrointestinal tract
Strongylus
equinus

+++
+++

+++
+++
+++
+++
+++

+++

+++
+++

and elimination of some BZDs explain their relatively short residence in

the body. Thus, more soluble compounds have a shorter residence in
+
o
–

–
–

comparison to less soluble BZDs, which are absorbed over prolonged

periods. Thiabendazole and CBZ, the most water-soluble of the ther-
strongyles

apeutic BZDs, are more extensively and rapidly dissolved in rumen fluid
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++

+++
+++

+++

+++
+++
Small

++

and are thus absorbed more rapidly in ruminants (McKellar and Scott,
L5

1990). The less soluble BZD compounds remain as a slurry in the re-
ticulorumen and are absorbed over prolonged periods and thus remain
strongyles

+++

+++

+++
+++

in the plasma for a longer time. Since an equilibrium exists between the
Small

plasma and the gastrointestinal tract, the duration of exposure of the

L4

+
+

+
+

+
–

–
–
–
–

gut parasites to effective concentrations of the drug is extended. At the

extreme limits of solubility anthelmintics may be less effective since
Oxyuris
equi L5

+++
+++
+++
+++
+++
+++
+++
+++
+++

+++

+++
+++
+++
+++
+++
++

they may not be absorbed sufficiently and are excreted unchanged in

–

the faeces. This may explain the difference between the plasma con-
centrations of FBZSO achieved following oral administration of FBZSO
Oxyuris
equi L4

+++

+++

+++
+++
+++
+++

+++
+++
+++
+++

as the parent drug compared to its residence following administration

+

+
+

o
–

of its interconvertible metabolite FBZ (Ngomuo, 1983). A large pro-

portion of the less soluble FBZ is known to be excreted directly in the
Probstmayria

faeces (Prichard, 1978; McKellar et al., 2002; Gokbulut et al., 2006).

vivipara

The pharmacokinetics of BZD anthelmintics has been studied in

+++
+++

+++
+++

+++

+++

+++
+++

horses in which the metabolic interconversion of the sulphide and

o

o
–

–
–
–

–
–

sulphoxide BZDs (FBZ and OFZ respectively) appears to differ sub-

35-40

stantially from that in ruminants (Marriner and Bogan, 1985). Sulphide

(mg/
Dose

200
kg)

2.5
8.8

6.6

0.2
0.4
50
20

10
10

10
75

40
60

and sulphoxide BZDs are known to bind nematode tubulin (Lacey et al.,
5

5
6

1987) and therefore have activity against nematodes although sul-

Thiabendazole
Cambendazole

Phenothiazine
Fenbendazole

Oxibendazole
Parbendazole
Mebendazole

Oxfendazole

Moxidectin*
Albendazole

Ivermectin*
Trichlorfon
Levamisole

phides exert inhibitory activity on tubulin at lower concentrations than

Dichlorvos
Piperazine
Febantel

Haloxon
Pyrantel

sulphoxides. Nevertheless, in most species examined the sulphoxide

Table 3

Drugs

moiety predominates in plasma and is thought to confer activity against

gut-dwelling nematodes following secretion across the gastrointestinal

32
C. Gokbulut, Q.A. McKellar
wall into the gut lumen where it may undergo sulpho-reduction.
There are significant differences in the pharmacokinetics of BZD
anthelmintics between monogastric and ruminant species (Marriner
and Bogan, 1981b; McKellar and Scott, 1990). In contrast to other
species (sheep, cattle, man), following treatment of FBZ or FBZSO
equine species generate relatively higher concentrations of the more
oxidised sulphone metabolite than of sulphoxide. This may be due to
the relatively rapid conversion of sulphoxide to the sulphone by the
equine liver (Marriner and Bogan, 1985). The low plasma concentra-
tions of active moieties (FBZ, FBZSO) following FBZ administration
probably accounts for the higher and repeated dosage required for the
treatment of migrating larval and tissue stages of strongyles and lung
worms (Marriner and Bogan, 1981a).
The BZD anthelmintic drugs have lower bioavailability in mono-
gastric animals (e.g. dog and horse), which have relatively faster gut
transit time than ruminants since rapid passage of food in the gut de-
creases the absorptive time for the drugs. Dougherty, (1992) reported
gut transit time of 8.47 h in horses. In ruminants, this time may range
from 30 to 80 h depending on the digestibility of food, since highly
digestible food has a shorter retention time (Warner, 1981). The sys-
temic bioavailability of most drugs administered orally is lower in
herbivorous species (horse and ruminants) than in dogs and cats. The
greater “first-pass effect” and higher drug metabolising capacity of the
reticulo-rumen and liver account for this effect. In ruminants, the op-
posite is true for BZD drugs. After oral administration to ruminants,
greater bioavailability is observed than in monogastric species because,
in ruminants, the relatively slower gut transit time conferred by the
forestomach reservoir means that BZDs are more extensively absorbed
than in monogastric animals (Baggot and McKellar, 1994). In addition,
FBZ or FBZSO were extensively absorbed when administered directly
into the cecum in horses (McKellar et al., 2002). The anatomy of the
equine ileo-cecal valve makes retrograde delivery of the drug into the
distal ileum from the cecum unlikely, although not impossible.
Previous studies in horses and donkeys indicated that the plasma
concentrations of FBZSO and FBZ were relatively low and that they are
extensively metabolised to their sulphone metabolite when each was
administered at10 mg/kg BW. In horses, after oral administration of
FBZSO at a dose of 10 mg/kg BW, the area under the curve (AUC) for
the parent drug and its metabolite FBZ were 4.36 and 1.40 μg h/mL
respectively (McKellar et al., 2002). In a similar study, carried out with
FBZ at the same dose rate, lower plasma concentrations of parent drug,
FBZ, and its metabolite FBZSO were obtained, with FBZSO being below
the limit of detection (< 0.04 μg/mL) and FBZ having an AUC of
1.77 μg h/mL (Marriner and Bogan, 1985). This reflects the better ab-
sorption and greater systemic availability of FBZSO compared to FBZ
since each compound produces the same metabolites and these would
be expected to have similar metabolic and excretory rates. It is of in-
terest that the AUC of the sulphide moiety was 2.3 times greater in
horses administered FBZSO than in horses given FBZ as the parent
molecule. The much higher solubility of FBZSO (3.01 mg/L) than that
of FBZ (0.07 mg/L) (Marriner and Bogan, 1985) may explain its greater
absorption at a rate exceeding its oxidative clearance and this may
provide sufficient substrate for reductive metabolism to the sulphide in
horses. The limited adsorption rate of FBZ may be matched by rapid
oxidative metabolism with consequent low concentrations achieved in
plasma following its oral administration.
In animals, diet can substantially affect the bioavailability of drugs.
Some non-steroidal anti-inflammatory drugs bind to food particles in
horses which delay the absorption of the drugs significantly (Lees et al.,
1988). Hennessy (1993) emphasised the role played by the adsorption
of BZDs on the ruminal particulate material in the extension of their
bioavailability in ruminant species. The physicochemical nature of drug
association with particulate material is likely to be due to physical
adsorption rather than specific chemical binding (Lees et al., 1988). In
sheep, the relative bioavailability of BZDs decreased when administered
concomitantly with food (Taylor et al., 1992). In cattle, it was
33
Veterinary Parasitology 261 (2018) 27–52
demonstrated that fasting or restricted feed intake increased the re-
lative bioavailability of ABZ metabolites (Sanchez et al., 1997). How-
ever, in the dog (McKellar et al., 1993a) feeding increased the bioa-
vailability of BZDs after oral administration. Although there were no
statistically significant effects of feeding on the absorption of FBZ
(10 mg/kg) in horses, the cumulative AUC for the active metabolic
moieties (FBZSO and FBZ) were four times as large in unfed than fed
horses suggesting that FBZ might be more effective in the horse fol-
lowing food restriction (Table 6) (McKellar et al., 2002).
Parasitic infections of the gastrointestinal tract have been demon-
strated to affect the bioavailability of anthelmintics in animals. In sheep
infected with Ostertagia circumcincta and treated with FBZ, plasma
concentrations of both FBZ and FBZSO were reduced when compared
with uninfected animals treated with the same dose of FBZ (Marriner
et al., 1985). Moreover, the plasma concentration of FBZSO was re-
duced by 25% in goats infected with the same nematode compared to
uninfected goats given the same dose of FBZSO (Bogan et al., 1987). In
contrast, after intraruminal administration of ABZ, the AUC of the
ABZSO was larger in sheep naturally and artificially infected with
Haemonchus contortus than in non-infected animals (Alvarez et al.,
1997). It has been shown that the pH of abomasal fluid was decreased
by the presence of nematode parasites (Mostofa and McKellar, 1989;
McKellar et al., 1990). In addition, helminthiasis produces a constant
stimulus for gastrin secretion leading to hypergastrinaemia and pro-
nounced hyperplastic changes in the abomasal mucosa (Anderson et al.,
1988). These changes probably affect absorption of BZDs in ruminants;
hence the pharmacokinetic behaviour and expected efficacy may be
reduced by the presence of the parasites. An elevation in gastric pH
causes a reduction in solubility of the BZDs and this would contribute to
decreased bioavailability. It has been reported that there is a reduction
in the bioavailability of the pro-BZD, FBT in lambs infected with Os-
tertagia, and in those infected with Trichostrongylus colubriformis there
was a reduction in intestinal motility and mucosal villous atrophy, both
of which could affect drug absorption (Debackere et al., 1993). The
pathophysiological changes associated with stomach parasites in the
horse have been less well studied and represent a less important group
of parasites than those infecting the abomasum in ruminants. It is likely
nevertheless, that stomach and intestinal parasites will have an effect
on the absorption of BZD’s in horses. Parasitic infection may also alter
drug metabolism, which could affect the disposition of the anthelmin-
tics. It has been shown that the enzymatic activity of the hepatic mi-
crosomal cytochrome P450-dependent monooxygenase system is de-
pressed in rats infected with F. hepatica (Tekwanl et al., 1988).
Similarly, in sheep, F. hepatica infection decreased sulphonation of ABZ
and this was related to a decline in liver microsomal P450-dependent
monooxygenase activity (Galtier et al., 1986). In contrast to these ob-
servations, there were no significant differences in the bioavailability of
anthelmintics (levamisole, Ivermectin, NTB and ABZ) in sheep infected
with Nematodirus battus and non-infected sheep (McKellar et al., 1991,
1993b). There does not appear to be available data on the effects of
parasitism on anthelmintic disposition in horses.
Oxibendazole is a member of BZD anthelmintic class with a broad
spectrum of activity against gastrointestinal helminths only, which has
been marketed for use in horses for many years. Gokbulut et al. (2002)
reported that the plasma concentrations of the parent OXB were rela-
tively very low following oral administration in horses (Table 4) and a
liver microsome study showed that OXB was metabolised extensively to
unidentified metabolites in horses. Gottschall and Wang (1996) re-
ported that in swine OXB was quickly metabolised and liver was the
only tissue which contained significant residue following oral admin-
istration at a dose of 15 mg/kg BW. It was reported that OXB has little
or no effect against migrating stages of S. vulgaris, or against T. axei, H.
muscae and D. megastoma (Kates et al., 1975; Nawalinski and
Theodorides, 1977). Interestingly OXB has been shown to have activity
against gastrointestinal parasites selected for resistance to other BZDs
(Uhlinger et al., 1986). High gastrointestinal concentrations of OXB
C. Gokbulut, Q.A. McKellar Veterinary Parasitology 261 (2018) 27–52

Table 4
Pharmacokinetic parameters of benzimidazole (BZD) anthelmintics in equine species following oral administration.
Pharmacokinetic parameters References

2
Species Benzimidazoles Abbreviations Tmax (h) Cmax (μg/mL) AUClast (μg.h/mL) AUMClast (μg. h /mL) T1/2λz (h) MRTlast (h)
(10 mg/kg)

Horse Fenbendazole FBZ 8.00 ± 2.70 0.04 ± 0.01 0.61 ± 0.11 9.33 ± 2.89 – 14.21 ± 1.74 (McKellar et al., 2002)
FBZSO 9.50 ± 3.52 0.01 ± 0.00 0.17 ± 0.02 2.26 ± 0.46 – 12.90 ± 1.33
FBZSO2 10.50 ± 3.20 0.06 ± 0.01 1.12 ± 0.19 12.54 ± 2.43 – 16.50 ± 1.00
FBZ 10.00 ± 7.38 0.11 ± 0.05 – – – – (Marriner and Bogan,
FBZSO2 12.00 ± 6.20 0.16 ± 0.08 – – – – 1985)
Oxfendazole OFZ 8.88 ± 3.02 0.35 ± 0.07 4.36 ± 0.89 69.07 ± 21.85 – 14.77 ± 2.32 (McKellar et al., 2002)
FBZ 13.50 ± 1.99 0.09 ± 0.02 1.40 ± 0.32 23.45 ± 6.98 – 15.58 ± 1.01
OFZSO2 12.00 ± 3.63 0.76 ± 0.09 13.00 ± 1.55 210.24 ± 45.84 – 15.45 ± 2.10
OFZ 7.20 ± 3.91 0.43 ± 0.13 7.10 ± 2.65 139 ± 60.0 10.4 ± 3.84 16.8 ± 6.99 (Bruni et al., 2005)
OFZSO2 16.9 ± 5.37 0.27 ± 0.12 5.88 ± 2.52 116 ± 75 4.58 ± 0.94 17.6 ± 3.97
Oxibendazole OXB 0.81 ± 0.53 0.01 ± 0.01 0.07 ± 0.05 – – 14.17 ± 3.82 (Gokbulut et al., 2002)
Netobimin ABZSO 10.50 ± 3.66 0.53 ± 0.14 8.63 ± 1.01 129.12 ± 20.10 5.97 ± 1.59 15.08 ± 2.50 (Gokbulut et al., 2009)
ABZSO2 19.50 ± 3.96 0.36 ± 0.09 8.21 ± 2.87 177.55 ± 74.17 7.44 ± 1.06 21.33 ± 2.31
Triclabendazole TCBZSO 8.00 ± 00 4.57 ± 1.11 115.00 ± 25 – 9.74 ± 00 – (Kinabo and Bogan,
(12 mg/kg) TCBZSO2 25.33 ± 6.67 13.15 ± 1.56 594.00 ± 97 – 17.65 ± 00 – 1989)
Donkey Oxfendazole OFZ 5.67 ± 2.89 0.49 ± 0.11 5.17 ± 0.82 58.12 ± 14.18 4.49 ± 0.74 10.95 ± 1.92 (Gokbulut et al., 2006)
FBZSO2 8.00 ± 2.53 0.60 ± 0.09 10.33 ± 0.87 161.00 ± 22.99 7.53 ± 0.35 15.38 ± 1.50
Albendazole ABZSO 5.71 ± 0.87 0.08 ± 0.01 0.84 ± 0.14 8.27 ± 1.86 6.65 ± 3.22 9.15 ± 1.20
ABZSO2 8.00 ± 2.31 0.04 ± 0.00 0.50 ± 0.11 5.68 ± 1.93 7.44 ± 1.19 9.98 ± 1.58
Mebendazole MBZ 7.33 ± 3.93 0.04 ± 0.01 0.78 ± 0.35 19.49 ± 7.86 11.97 ± 4.38 20.34 ± 7.59 (Gokbulut et al.,
(10 mg/kg) 2016a)
Mebendazole MBZ 8.00 ± 0.00 0.07 ± 0.01 1.42 ± 0.20 33.78 ± 10.38 13.13 ± 3.85 23.43 ± 5.55
(20 mg/kg)
Triclabendazole TCBZSO 9.33 ± 1.33 4.34 ± 0.86 100.00 ± 16 – 9.40 ± 00 – (Kinabo and Bogan,
(12 mg/kg) TCBZSO2 12.00 ± 00 2.94 ± 0.44 63.00 ± 6.00 – 9.06 ± 00 – 1989)
Pony Triclabendazole TCBZSO 26.67 ± 2.67 4.01 ± 0.25 157.00 ± 20 – 10.91 ± 00 –
(12 mg/kg) TCBZSO2 29.33 ± 2.67 13.00 ± 2.30 710.00 ± 81. – 23.08 ± 08 –

Cmax: peak plasma concentration; Tmax: time to reach peak plasma concentration; AUClast: area under the (zero moment) curve from time 0 to the last detectable
concentration, MRT: mean residence time; T1/2λz: terminal half-life, AUMC: area under the first moment curve.

observed from a faecal study could be effective for adult stages of most
parasitic nematodes that inhabit in the gastrointestinal tract. Never-
theless, low plasma concentrations of OXB are unlikely to be effective
against migrating larval and tissue stages of nematodes (Gokbulut et al.,
2002). It is likely that high first-pass metabolism decreases OXB
availability in the plasma of horses and it seems unlikely that phar-
macokinetic characteristics can explain the sustained activity of OXB
against resistant nematodes since it has characteristics which ought to
confer poorer activity against nematodes compared to other members
of this anthelmintic class. It is possible that the OXB exerts its effects on
resistant nematodes as a consequence of its affinity for tubulin (Lacey
and Watson, 1985). The metabolic inhibition of OXB by co-adminis-
tration with piperonyl butoxide (PB) previously indicated for FBZ and
OFZ could be a strategy to extend the exposure of nematodes to the
parent active moiety and thus to improve the efficacy of OXB in horses.
The gastrointestinal environment of equine species has a great re-
ductive capacity for BZD compounds. It has been shown that the BZD
anthelmintics licensed for use in horses in some countries (e.g. FBZ,
OFZ and OXB) have relatively poor systemic availability, since they are
extensively metabolised to their inactive metabolites by gastrointestinal
microflora and/or first-pass metabolism compared to ruminant species
(Gokbulut et al., 2002; McKellar et al., 2002; Gokbulut et al., 2006).
The detailed characterization of the kinetic behaviour and metabolic
pathways of a pro-BZD, NTB, has markedly contributed to its optimized
use in ruminants. Although, NTB is not licensed for use in equine spe-
cies, the anthelmintic efficacy, plasma disposition and faecal excretion
of NTB, and its metabolites (ABZ, ABZSO and ABZSO2), at 10 mg/kg
were determined by Gokbulut et al. (2009) in horses after oral treat-
ment. This study indicated that NTB was not detectable in any plasma
or faecal samples; however, ABZ was predominant in the faeces. Ne-
tobimin produced similar metabolites and disposition in horses com-
pared with ruminant species. This suggested an efficient conversion of
the pro-drug NTB into the active form ABZ in the reductive
environment of the gastrointestinal tract of horses. It has been shown
that following intraruminal or oral administration, NTB is reduced to
ABZ in the gastrointestinal tract of cattle and sheep (Lanusse and
Prichard, 1990; Lanusse et al., 1993). Some pharmacokinetic para-
meters of BZD anthelmintics (FBZ, FBZSO, OXB and NTB) previously
studied in horses are shown in Table 4. These studies reported that FBZ
or its active sulphoxide metabolite, FBZSO and OXB displayed relatively
low plasma concentration, and were quickly metabolised to their in-
active sulphone metabolites which predominated in plasma, whereas in
the NTB study, active ABZSO is predominant and displayed higher
plasma disposition compared to ABZSO2 after NTB administration.
These differences could be due to relatively slow oxidation of ABZSO to
ABZSO2 in equine species (Gokbulut et al., 2006, 2009).
There is a paucity of data available on the pharmacokinetics or ef-
ficacy of anthelmintics used in donkeys, as donkeys are an often-ne-
glected species. Different classes of drugs used in horses and ruminants
are commonly extrapolated for use in donkeys without optimization of
dosing regimens and determination of pharmacokinetic and pharma-
codynamic properties. It has been reported that donkeys have a greater
capacity to metabolize certain drugs compared with horses; and al-
though there are some exceptions, higher dosage or shorter intervals
could be required in order to reach and maintain effective drug con-
centrations (Matthews et al., 1997; Kum et al., 2009; Grosenbaugh
et al., 2011; Sekkin et al., 2012). Gokbulut et al. (2006a) reported that
the systemic availability of FBZSO was significantly greater than that of
FBZ and ABZ following oral administration at same dose rate in don-
keys. This probably reflects better water solubility and absorption of
FBZSO than FBZ and ABZ since the same metabolites are produced by
each compound and these would be expected to have similar metabolic
and excretory rates. Although, the plasma dispositions of FBZSO and its
sulphone metabolite in donkeys showed a similar profile to that in
horses (Marriner and Bogan, 1985; McKellar et al., 2002). Unlike
horses, FBZ and its sulphoxide and sulphone metabolites were not

34
C. Gokbulut, Q.A. McKellar
detected in the plasma of donkeys at any time. It is likely that FBZ
absorption from the gastrointestinal track is substantially lower in
donkeys than horses and larger faecal excretion of FBZ than FBZSO and
ABZ supports this finding. The higher solubility of FBZSO (3.01 mg/L)
than of FBZ (0.07 mg/L) (Marriner and Bogan, 1985) may explain its
greater absorption in donkeys. It is also apparent that the sulphone and
sulphoxide metabolites were predominant in plasma following admin-
istration of FBZSO and ABZ in donkeys. It was demonstrated that horses
metabolize FBZ and FBZSO to their sulphone metabolites more quickly
than ruminants (Marriner and Bogan, 1985; McKellar et al., 2002).
Although the bioavailability of ABZ was lower than in ruminants, its
metabolic products displayed a similar profile to ruminants. Plasma
dispositions of ABZ displayed a different profile compared to those of
FBZSO and FBZ in donkeys. Although, the parent ABZ was not detected
in plasma, its sulphoxide and sulphone metabolites appeared in plasma
following oral ABZ administration. In addition, Cmax and AUC of the
sulphoxide metabolite (0.08 μg and 0.84 μg h/mL, respectively) which
is thought to be anthelmintically active were significantly higher and
larger, respectively than that of the sulphone metabolite (0.04 μg/mL
and 0.5 μg h/mL, respectively) which is thought to be anthelmintically
inactive (Gokbulut et al., 2006).
It has been reported that the time until the maximum faecal con-
centrations (32 h for FBZSO, 34 h for FBZ and 30 h for ABZ) were longer
in donkeys compared to horses (24 h for FBZ and FBZSO) reflecting
slower gut transit time following oral administration in donkeys
(McKellar et al., 2002; Gokbulut et al., 2006). It is likely that hay-based
diet and different anatomic characteristics caused this difference
(Gokbulut et al., 2006). In sheep and cattle, it was reported that the
reduction of FBZSO to its sulphide (FBZ) occurred in ruminal fluid
(Beretta et al., 1987). The reductive environment of the gastrointestinal
tract of the donkey is likely to be responsible for similar metabolic re-
duction in that species. Following FBZ administration, the parent drug
was predominant in faecal samples and its sulphoxide metabolite was
found in extremely low concentrations. Following ABZ administration
its sulphoxide metabolites were detected at significantly greater con-
centrations in faeces than FBZSO following FBZ administration. The
extremely poor water solubility of FBZ may be the reason for this since
it is likely that absorption and oxidative metabolism are necessary to
generate FBZSO and this will be restricted for drugs undergoing
minimal dissolution. In addition, following FBZSO administration, the
parent molecule was extensively metabolised to its sulphide metabolite
(FBZ) which displayed a greater faecal excretion profile than that of the
parent FBZSO. Interestingly the sulphide metabolite was not detected in
any plasma samples and it is possible that high first-pass metabolism
decreased the sulphide metabolite bioavailability by converting back to
parent FBZSO. In other words, the rate of sulphoxidation in liver ex-
ceeded the rate of gastroenteric reduction and absorption of the parent
FBZSO. This may explain why the bioavailability of FBZSO was sig-
nificantly greater than that of FBZ and ABZ following oral administra-
tion at the same dose rate in donkeys.
Recently, the plasma disposition, milk excretion and anthelmintic
efficacy of MBZ were investigated in donkeys following oral adminis-
trations at 10 mg/kg and 20 mg/kg BW (Gokbulut et al., 2016a). A
dose-dependent plasma disposition of MBZ was observed (Table 4). At a
dosage of 10 mg/kg BW, MBZ was not detected in any milk samples.
However, MBZ reached peak milk concentration of 0.01 μg/mL at
10.66 h and AUCmilk/AUCplasma value was 0.18 ± 0.02 following
20 mg/kg BW. Mebendazole appears to have a minimal disposition in
milk suggesting that it may be used in lactating donkeys and that a zero
milk-withdrawal period might be appropriate in this species, although
further work on metabolism in this species would be necessary before a
maximum residue limit could be set. The results of a faecal egg count
reduction (FECR) test for both MBZ dosages indicated high efficiency
(> 95%) until day 28 after treatment. The trial demonstrated that MBZ
oral paste at the horse dosage (10 mg/kg BW) was effective for the
treatment of cyathostomins in donkeys and it is likely that a similar
35
Veterinary Parasitology 261 (2018) 27–52
dosage regimen of MBZ could be used for horses and donkeys (Gokbulut
et al., 2016a).
The plasma dispositions of MBZ (Gokbulut et al., 2016a) was dif-
ferent from those of FBZ, FBZSO and ABZ (Gokbulut et al., 2006) stu-
died in donkeys at the same dosages (Table 4). The peak plasma con-
centrations and areas under the curve of OFZ (Cmax: 0.49 μg/mL, AUC:
5.17 μg.h2/mL) and ABZ (Cmax: 0.08 μg/mL, AUC: 0.84 μg h2/mL) were
higher than those of MBZ (Cmax: 0.04 μg/mL, AUC: 0.78 μg.h2/mL),
respectively. Nevertheless, the T1/2 (11.97 h) and MRT (20.34 h) values
of MBZ are much longer compared with those of FBZSO (T1/2: 4.49 h,
MRT: 10.95 h) and ABZ (T1/2: 6.65 h, MRT: 9.15 h) at the same dosage
(10 mg/kg). These differences probably reflect lower water solubility
and subsequent lower absorption of MBZ compared with FBZSO and
ABZ but subsequent slower metabolism and excretion of the MBZ which
has been absorbed. Similarly, low systemic availability has been ob-
served with MBZ in humans and it has been suggested that this is a
result of a very low level of absorption of MBZ from the gastrointestinal
tract (Munst et al., 1980).
The plasma disposition of MBZ in donkeys also differs substantially
from those observed in sheep and goats in which higher concentrations
are observed (Galtier et al., 1994). The reason for the lower systemic
exposure in donkeys compared with that observed in ruminant species
is probably related to differences in the physiological or anatomic
properties between the animal species (McKellar and Scott, 1990). The
benzimidazole anthelmintic drugs have lower bioavailability in mono-
gastric animals (e.g. dog and horse), which have relatively faster gut
transit time than ruminants since and rapid passage of food in the gut
causes a decrease in the bioavailability of the drugs.
Kinabo and Bogan (Kinabo and Bogan, 1989) studied the plasma
dispositions of TCBZ and its sulphone and sulphoxide metabolites in
horses, ponies and donkeys after oral administration of the drug at the
dose (12 mg/kg BW) recommended for ruminant species (Table 1). In
this study, the AUC values of the sulphoxide (TCBZSO) were about 5
times lower in equines compared to ruminant species (Kinabo and
Bogan, 1988). From this, it could be inferred that triclabendazole is less
well absorbed in equine than in ruminant species. This could be at-
tributed to factors such as variations in pH of the gastrointestinal
contents, gastrointestinal transit times and digestive tract capacities.
Because the sulphoxide concentrations may be a more accurate reflec-
tion of likely flukicidal activity, it would seem that a relatively higher
dose of triclabendazole may be required in equine species (Kinabo and
Bogan, 1989). Moreover, significant differences between donkeys and
horses and ponies were observed for the sulphone metabolite of TCBZ
whereby the Cmax and the AUC in donkeys were lower than in horses
and ponies (Table 4). It is probable that donkeys are capable of ex-
creting the sulphone more efficiently than horses and ponies. Never-
theless, these differences may be of little therapeutic significance be-
cause the sulphone metabolite is generally devoid of anthelmintic
activity (Kinabo and Bogan, 1989).
2.5.1. Potentiation of BZDs anthelmintics
It is likely that metabolic inhibition will be more effective than
simply increasing the dose rate in order to improve the efficacy of BZDs,
since their pharmacokinetics in some monogastrics are dose-in-
dependent and absolute bioavailability cannot be increased by in-
creasing the dose (McKellar et al., 1993a). The potentiation of the ac-
tivity of benzimidazoles and pro-benzimidazoles has been achieved by
the co-administration with metabolic inhibitors, which are thought to
act principally by improving the pharmacokinetic profiles of the active
moieties of the administered drug. The potentiating agents for the BZDs
and pro-BZDs may be useful in practice since an increase in the ratio of
sulphide + sulphoxide: sulphone metabolites occur, and the less oxi-
dised metabolites (sulphide) of the BZDs are considered to exhibit
greater binding to nematode tubulin (Lacey et al., 1987).
Two main microsomal enzymatic pathways have been proposed as
responsible for the sulphoxidation of sulphur containing BZDs including
C. Gokbulut, Q.A. McKellar
ABZ, OFZ and TCBZ. The flavin-containing mono-oxygenase (FMO)
enzymatic system is responsible for sulphoxidation (Galtier et al., 1986)
whereas the hepatic cytochrome P450 metabolic pathway is probably
responsible for the oxidation of BZ-SO to BZ-SO2 metabolite
(Souhailielamri et al., 1988). Metabolic inhibitors such as methimazole
which inhibits flavin-containing mono-oxygenase and metyrapone
which inhibits cytochrome P450 prevent the oxidative metabolism of
NTB and ABZ sulphoxide thus improving the efficacy of these anthel-
mintics and pharmacokinetic profile of the active metabolites (Lanusse
and Prichard, 1992a,b). The bioavailability of anthelmintic metabolites
was also improved when FBZ and FBZSO were co-administered with
methimazole (Lanusse et al., 1995). Co-administration of PBZ with
FBZSO has been shown to increase the anthelmintic activity of FBZSO
and confer activity against BZD-resistant nematodes. This has been at-
tributed to a reduction in hepatic biotransformation and biliary secre-
tion of FBZSO. Parbendazole promotes an increase in extra-biliary
transfer of FBZSO into the intestinal lumen and thus exposure of the
parasites to increased drug concentrations in the gastrointestinal lumen
(Hennessy et al., 1992).
Benchaoui and McKellar (1996) have shown that PB co-adminis-
tration greatly improves the activity of FBZ against nematodes resistant
to BZDs in sheep when administered at normal therapeutic doses. The
methylenedioxyphenyl compound PB is a potent inhibitor of the cyto-
crome P450 oxidation of BZD sulphoxides to sulphones and it was
shown to reduce the metabolism of FBZ in cultured rat hepatocytes by
50% in 24 h (Benchaoui and McKellar, 1996). It was demonstrated that
the major route of metabolism of PB involved the opening of the me-
thylenedioxy ring followed by loss of the methylene group into the
endogenous metabolic pool (Cockburn and Needham, 1999). This is
also believed to be the basis of the initial inhibition of the cytochrome
P450 enzyme system, which is essential for the compound’s efficacy as
a synergist. Current evidence suggests that it is the carbene inter-
mediate formed with the methylene group that complex with the Fe++
ion of cytochrome P450 (Wilkinson et al., 1984; de Montellano and
Reich, 1986) that induces its effect. Piperonyl butoxide has shown
isozyme specificity in rats using different probe drugs for hepatic drug-
metabolising activity (Bachmann, 1989). In sheep, it was demonstrated
that co-administration of PB with FBZ significantly enhanced the
pharmacokinetic profile and potentiated the anthelmintic activity of the
BZDs. A dose-dependent inhibition of FBZ sulphoxidation by PB im-
proved the efficacy of the drug against nematodes of sheep, including
BZD-resistant O. circumcincta and H. contortus (Benchaoui and McKellar,
1996). The co-administration of PB significantly increased the AUC and
Cmax of FBZ in fed and unfed horses (McKellar et al., 2002). In fed
horses PB co-administration increased the AUC of the active moieties
FBZSO and FBZ by 13.9 times and 13.2 times respectively (Table 6). In
unfed horses PB increased the AUC of the parent FBZ by 11 times but
decreased the AUC of the FBZSO moiety by 2.3 times (McKellar et al.,
2002). It has also been shown that PB significantly inhibited the me-
tabolism of OFZ and the parent molecule and its sulphide metabolite
(FBZ) achieved much greater plasma concentrations (AUC and Cmax)
following intravenous administration of OFZ with PB in ponies
(McKellar et al., 2002). Bruni et al. (2005) also showed that co-ad-
ministration with PB significantly improved the pharmacokinetic pro-
file of OFZ in horses. The significantly greater AUC (4.25 times) and
Cmax (2.6 times) values of OFZ observed in the OFZ + PB treated horses
correlate with a PB interference of OFZ sulphonation. Piperonyl but-
oxide also increased the AUC value for FBZSO2 by almost 2 times and
this could be related to the higher concentration of OFZ observed in the
OFZ + PB treated horses, resulting in a greater substrate concentration
available for sulphonation when the sulphonating inhibitory effect of
PB elapsed (Bruni et al., 2005). In addition, these outcomes also cor-
related with in vitro studies undertaken in liver microsomes from horses
which indicated that PB inhibited significantly the metabolism of OFZ,
FBZ and OXB (Gokbulut et al., 2002; McKellar et al., 2002).
These studies demonstrated the very great potential for synergy of
36
Veterinary Parasitology 261 (2018) 27–52
BZD sulphides and sulphoxides when combined with PB. It is antici-
pated that the synergistic effects demonstrated could have major posi-
tive benefits for greater drug exposure of the target parasites and for the
treatment of BZD resistant parasites in equine species. These findings
have also indicated that PB had a more dramatic synergistic effect on
the plasma dispositions of BZDs in horses compared to that in rumi-
nants, probably because equine species oxidise BZD sulphides to
sulphoxide more rapidly than ruminants (McKellar et al., 2002).
2.5.2. Stereospecific dispositions of BZD anthelmintics
Enantioselective or chiral compounds are extensively used in ve-
terinary practice. Pharmacodynamic and pharmacokinetic properties of
enantiospecific pairs are commonly different and are of major im-
portance for their effective and safe therapeutic use (Delatour et al.,
1994).
Sulphur-containing BZD anthelmintics (FBZ, OFZ or FBZSO and
ABZ), form a chiral centre about the sulphur atom when administered
as sulphoxides (FBZSO) or when metabolised into their respective
sulphoxides (FBZSO, ABZSO), they are subsequently metabolised into
sulphones metabolites which are anthelmintically inactive, whereas
sulphides and sulphoxides are both active. The stereospecific behaviour
of BZD sulphoxides has been investigated in the plasma of various
species following administration of the prochiral sulphide parent mo-
lecule (Delatour et al., 1990, 1991b). In sheep, the ratio of FBZSO en-
antiomers changed from 1.8 to 6.7 between 9 h and 120 h, and alben-
dazole sulphoxide (ABZSO) enantiomer ratio changed from 3.3 to 22.4
between 3 h and 36 h. The enantiospecific ratio of AUC values of
sulphoxide metabolites, following administration of sulphides, was
26:74 for FBSO and 14:86 for ABZSO enantiomers (Delatour et al.,
1990). The stereospecific behaviour of ABZSO was shown to be dif-
ferent between monogastrics and ruminants (Delatour et al., 1991a, b).
The enantiospecific ratio (+/-) of plasma concentration of ABZSO
changed over time in favour of (+) in all species examined, with the
exception of rats, and the initial (+) / (−) plasma ratio was close to a
racemate (50:50) in monogastrics but was 75:25 in sheep. These results
were confirmed by incubation of liver microsomes using ABZ as the
substrate (Galtier et al., 1986; Moroni et al., 1995). It is thought that the
FMO is mainly responsible for sulphoxidation, whereas cytochrome-
dependent monooxygenase is responsible for sulphonation (Benoit
et al., 1992). The initial enantiospecific ratio was 30:70 when co in-
cubated with methimazole (an inhibitor of FMO) and 65:35 in the
presence of clotrimazole (an inhibitor of cytochrome P450). These data
indicate that the FMO is product stereoselective and produces (+)
ABZSO, whereas cytochrome specifically uses (−) ABZSO as substrate
(Moroni et al., 1995). Both systems act equally in rats and probably in
other monogastrics (man, dog, horse), while the FMO system is pre-
dominant in ruminants. Differences of interspecies stereoselectivity for
the BZD sulphoxides exist and may be explained by different relative
enzyme contributions.
The chiral dispositions of OFZ and ABZ have been studied in vitro
and in vivo in equine species (McKellar et al., 2002; Bruni et al., 2005;
Gokbulut et al., 2009). It has been confirmed that FBZSO displayed
enantioselective pharmacokinetics since the (+) FBZSO enantiomer
predominated following administration of the racemate, and the (+)
FBZSO / (−) FBZSO ratio was 60:40 throughout most of the disposition
period (McKellar et al., 2002). In addition, after oral administration of
NTB in horses, the enantiospecific ratio (−/+) of ABZSO in plasma
remained in favour of (−) for the first 16 h but changed in favour of the
(+) enantiomer after 20 h following administration (Gokbulut et al.,
2009). This difference in the ratio may affect the anthelmintic activity
of the enantiomers, since it has been shown that the (-) ABZSO is
quickly metabolised into the inactive sulphone metabolite (Goudah,
2003) in sheep. Moreover, Alvarez et al. (1999, 2000) have reported
that the main enantiomer taken up by F. hepatica was (+) ABZSO fol-
lowing ABZ administration in infected sheep. For sulphur-containing
BZDs, the metabolism of sulphide to sulphoxide is thought to be
C. Gokbulut, Q.A. McKellar
principally catalysed by the FMO system (Galtier et al., 1986) whereas
metabolism of sulphoxide to sulphone is thought to be catalysed by
hepatic cytochrome P450 (Souhailielamri et al., 1988).
It has been shown that the co-administration of PB dramatically
altered the enantioselective pharmacokinetics of FBZSO since the (-)
FBZSO enantiomer predominated for the first 12 h following adminis-
tration after which the ratio changed in favour of (+) FBZSO (McKellar
et al., 2002). The in vitro studies with equine liver microsomes support
much of the in vivo work described above. Piperonyl butoxide sig-
nificantly inhibited the sulphonation of FBZSO and the sulphoxidation
and sulphonation of FBZ. It was also apparent that (-) FBZSO was me-
tabolised more rapidly than (+) FBZSO in equine liver microsomes and
that PB altered the metabolism such that the ratio of (+) FBZSO / (-)
FBZSO remaining after incubation was much closer to unity. Moreover,
Bruni et al. (2005) indicated that following administration of OFZ
alone, the AUC value of (-) FBZSO was 2-fold higher than that obtained
for (+) FBZSO (AUC ratio FBZSO (-) / (+) 2.03). However, after
treatment with OFZ + PB the ratio decreased by 32% (1.37). The
combination produced a significant enhancement of (+) FBZSO en-
antiomer concentrations, which could correlate with the selective in-
hibition by PB of the CYP450 system associated with the formation of
the (+) antipode (Bruni et al., 2005). The eudismic (potency) ratio of
FBZSO is unknown, however the alterations in enantiomer generation
together with the alteration in achiral metabolism of BZDs by PB could
have a major impact on the efficacy of BZD sulphides and sulphoxides
in the horse.
3. Imidazothiazoles and tetrahydropyrimidines
The anthelmintic properties of imidazothiazole derivatives were
discovered firstly in the early 1960s. The racemic compound tetra-
misole was synthesized in 1964 and then used widely for the treatment
of helminth infections in animals (Amery and Bruynseels, 1992). The
greater anthelmintic activity of the levo-isomer of tetramisole was
discovered in 1966 and the single isomer developed as the product
called levamisole (LVM) which has a broad spectrum anthelmintic ac-
tivity against a wide variety of gastrointestinal nematodes in domestic
animals. Recently, LVM has been categorised as a “multi-faceted drug”
(Gupta, 2016), and has been used not only for the treatment of gas-
trointestinal nematodes and lungworms in different animal species
(Miller, 1980), but also as an immunomodulator and adjuvant to treat a
variety of diseases including cancer, rheumatoid arthritis and different
dermatological disorders including viral and bacterial infections and
inflammatory skin diseases in human medicine (Biswajit et al., 2014).
Early studies indicated that LVM was not a suitable anthelmintic
compound for horses since it had a low efficacy against important ne-
matodes and had a poor therapeutic ratio resulting in some adverse
drug reactions including profuse sweating, lacrimation and hyper-
excitability (DiPietro and Todd Jr, 1987).
Tetrahydropyrimidines are imidazothiazole derivatives (Fig. 3) and
include pyrantel (PYR), morantel and oxantel used to control gastro-
intestinal parasites in domestic animals. Among these compounds, only
PYR has been licensed and used extensively in horses as an oral paste or
granules at a therapeutic dose of 6.6–13.2 mg/kg following single oral
administration for the treatment of gastrointestinal parasites. Recently,
the use of PYR in horses has increased due to the worldwide spread of
anthelminthic resistance against benzimidazole agents. It has been
shown that the anthelmintic activity of PYR salts is directly related and
proportional to the presence of its free base amount (Sheehan et al.,
2016).
3.1. Chemistry and metabolism
Pyrantel (1,4,5,6-tetrahydro-1-methyl-2-(2-(2-thienyl)ethenyl) pyr-
imidine) is available as a pamoate (syn. embonate) salt, which is almost
insoluble in water, and as a tartrate, which is soluble in water (180 mg/
37
Veterinary Parasitology 261 (2018) 27–52
mL). It differs from morantel by absence of a methyl group on the
thiophene ring (Fig. 3). Pyrantel pamoate is available as a ready-to-use
suspension and paste for oral use in horses. It is poorly absorbed from
the gastrointestinal tract since 50%–70% of an ingested dose is excreted
in the faeces (Arundel, 1983), and blood levels do not exceed 1 μg/mL
(Davis, 1973). Reduced systemic absorption of PYR potentially in-
creases availability in the lumen of the intestine (Bjorn et al., 1996).
Pyrantel pamoate is available in different formulations in different
jurisdictions as a paste for oral administration in horses and it is
available as a suspension for oral or nasogastric administrations and
mixing with feed. A pellet formulation of PYR tartrate is available for
administration in feed (DiPietro and Todd Jr, 1987). The solid form of
PYR salts are stable but their suspensions in water are degradable, re-
sulting in a reduction of their potency.
Pyrantel has been shown to be extensively metabolised to more
polar metabolites in cattle, sheep, dogs and rats by three metabolic
pathways; oxidation of the thiophene ring, oxidation of the tetra-
pyrimidine ring and mercapturic acid conjugation (Faulkner et al.,
1972). Furthermore the, N-methyl-1,3-propanediamine skeleton of the
tetrahydropyrimidin ring has been shown to be relatively resistant to
metabolism, as evidenced by its formation after hydrolysis in both urine
and body tissues, while hydroxylation of the thiophene ring is the main
route of metabolism of PYR (Faulkner et al., 1972). It is thought that the
polar metabolites of PYR excreted by urine and bile are anthelminti-
cally inactive (Lanusse and Prichard, 1993).
3.2. Efficacy and spectra of activity
In horses, PYR is the most widely used anthelmintic among the
tetrahydropyrimidines. The anthelmintic activity of PYR against
common gastrointestinal helminths in equine species is shown in
Table 3. Generally, PYR has a great efficacy against adult nematodes
in the gastrointestinal lumen and shows less activity against migrating
or encysted larvae and developing forms (Bogan and Armour, 1987).
Pyrantel is highly effective (95%–97%) against adult cyathostomins,
P. equorum and S. vulgaris, and has moderate activity against S.
edentatus (70%) and O. equi (65%) (Mirck, 1985). PYR is not effective
against Gasterophilus spp., but it has activity against the Anoploce-
phalan tapeworms if used at 13.2 mg/kg (Theodorides, 1985). It was
reported that PYR pamoate paste formulation was highly effective
(95–98%) against mature infections of Anoplocephala perfoliata in
horses and ponies following oral administration at a dosage of
13.2 mg/kg, BW (Owen and Slocombe, 2004). Continuous low-level
daily administration of PYR tartrate to horses was highly effective
against common gastrointestinal parasitic infections of horses, in-
cluding large strongyles (S. vulgaris, S. edentatus and Triodontophorus
spp.), adult cyathostomins (Cyathostomum spp., Cylicocyclus spp., and
Cylicostephanus spp.), and adult and fourth-stage P. equorum (Valdez
et al., 1995). Recently, daily administration of PYR tartrate in feed (at
a dose of 2.64 mg/kg/day) significantly reduced numbers of adult
cyathostomins in the gut lumen and early third-stage larvae in the
cecal mucosa and, increased the proportions of fourth-stage larvae in
the gut contents in horses (Reinemeyer et al., 2014). Daily PYR tar-
trate administration in ponies was highly effective against strongyles
and significantly reduced the strongyle egg and pasture larval counts
during a grazing season (Slocombe and Lake, 2007). In addition, PYR
pamoate was highly effective against O. equi (Reinemeyer et al.,
2010b) and an endectocide-resistant isolate of P. equorum
(Reinemeyer et al., 2010a) at a dose of 13.2 mg/kg following the paste
formulation administration in horses. However, some investigations
from different countries have reported the emergence of PYR re-
sistance in horses (Brazik et al., 2006; Slocombe and de Gannes,
2006). Recently, it has been observed that the efficacy of PYR against
Strongylus spp. reduced in five groups of yearlings (FECR range:
0–73%), but PYR was found to be highly efficacious in mares (FECR
range: 98–99.4%) at a dose of 19 mg/kg following the oral
C. Gokbulut, Q.A. McKellar
Fig. 3. Chemical structures of imidazothiazole anthelmintic compounds (LVM and tetrahydropyrimidines).
administration in horses (Relf et al., 2014). However, PYR pamoate is
not labelled for efficacy against luminal, fourth stage cyathostomin
larvae.
It has been demonstrated that PYR pamoate had a good anthel-
mintic efficacy (> 90%) against strongylidea in donkeys (Napoli et al.,
2013). Recently, a therapeutic equivalence was demonstrated for paste
and granule formulations of PYR based on FECR test in donkeys
(Gokbulut et al., 2014). PYR pamoate paste and granule formulations
were highly efficacious (> 95% efficacy) against intestinal strongylidae
following oral administration at a dosage of 6.94 mg/kg of BW in
donkeys. Moreover, the results obtained in both treated groups were
consistent with the currently approved label claim for PYR oral for-
mulations against intestinal strongyle parasites of horses. Although, the
granule formulation displayed higher plasma concentrations and
availability compared to the paste formulation, the difference in the
formulations of PYR did not seem to alter the anthelmintic efficacy in
donkeys.
3.3. Mode of action
LVM and tetrahydropyrimidines including PYR share similar mode
of action whereby they act selectively as agonists at synaptic and ex-
trasynaptic nicotinic acetylcholine (ACh) receptors on muscle cells of
susceptible nematodes. They produce contractions and spastic paralysis
in the parasites, which serve to eliminate them from the host (Martin,
1997; Martin and Robertson, 2007). Simultaneous application of acet-
ylcholine and PYR showed that both agonists acted on the same nico-
tinic receptors (Harrow and Gration, 1985) and that PYR is up to 100
times more potent than acetylcholine in inducing muscular contraction
(Aubry et al., 1970). It has been shown that PYR increases membrane
conductance and depolarizes the membrane by opening non-selective
ion channels that are permeable to both Na+ and K+ (Harrow and
Gration, 1985). Moreover, the biophysical and some pharmacological
properties of ACh receptors in nematode muscles are similar to the
neural receptor channels in mammalians, but, there are significant
pharmacological differences between nematodes and mammals, LVM
and PYR display selective therapeutic effects on the nematode muscle
receptors, minimizing their toxic effects on host muscle (Martin and
Robertson, 2007).
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Veterinary Parasitology 261 (2018) 27–52
3.4. Safety and toxicity
The oral LD50 values are for PYR tartrate 175 mg/kg in mice and
170 mg/kg in rats (Bossche, 1985) and are much lower compared to
PYR pamoate which has an oral LD50 above 2000 mg/kg in rats, mice
and dogs (EMEA, 1998). First signs of toxicities associated with PYR
tartrate were observed at a dose rate of 55 mg/kg and consisted of
sweating, dyspnea and even death (Cornwell and Jones, 1968). In
horses, no adverse effects occurred at doses up to 20 times greater than
the therapeutic dose of PYR pamoate (embonate) (Slocombe and Smart,
1975). No adverse effects were observed and PYR was well tolerated in
horses following a single oral administration of a paste and suspension
formulation of PYR pamoate at the recommended dose or repeated
dosing at 19.1 mg/kg BW with a 2- to 4-week dosing interval (EMEA,
1998). The maximum tolerated oral dose of PYR tartrate in sheep was
173 mg/kg (Austin et al., 1966) although the toxicity of PYR tartrate in
water in adult sheep varies according to the method of administration
(Cornwell, 1966). It has been reported that no acute toxicity was ob-
served in nine ponies which received oral PYR tartrate at doses of
50 mg/kg and 75 mg/kg BW, but one of three ponies died at a dose of
100 mg/kg BW (Cornwell and Jones, 1968).
The reproductive performance of stallions and pregnant mares was
not affected by PYR (Bentley et al., 1978). Teratogenicity studies con-
ducted in rabbits and rats indicated that there was no evidence of ter-
atogenicity, fetotoxicity or maternal toxicity of PYR pamoate following
daily oral administration at 9 mg/kg and 90 mg/kg BW (EMEA, 1998).
3.5. Pharmacokinetics
Although, PYR has been used as an anthelmintic drug for almost a
half century, there is a paucity of data available in the literature on the
pharmacokinetics of different formulations in domestic animals in-
cluding equine species. Different salts of PYR have different pharma-
cokinetic properties and consequently different toxicities to the host.
The pamoate (embonate) salt is almost insoluble in water and poorly
absorbed from the gastrointestinal tract and most passes unchanged in
the faeces (Arundel, 1983). Reduced systemic absorption of the
pamoate (embonate) form potentially increases availability in the
lumen of the intestine (Bjorn et al., 1996). The tartrate salt of PYR is
soluble in water and absorbed rapidly and extensively from the
C. Gokbulut, Q.A. McKellar
Table 5
Pharmacokinetic parameters of pyrantel (PYR) in equine species following oral
administration.
Species Horse Donkey
Formula paste paste granule
Dose (mg/kg) 13.3 6.94 6.94
Cmax (μg/mL) 0.09 ± 0.03 0.09 ± 0.02 0.21 ± 0.07
Tmax (h) 7.50 ± 1.41 14.86 ± 5.52 14.00 ± 9.45
AUClast (μg h/mL) 1.06 ± 0.24 2.65 ± 0.81 5.60 ± 0.59
T1/2λz (h) 13.43 ± 1.38 12.39 ± 5.35 14.86 ± 5.59
MRT (h) 11.99 ± 1.30 24.80 ± 5.54 25.44 ± 10.68
References (Gokbulut et al., 2001a) (Gokbulut et al., 2014)
Cmax: peak plasma concentration; Tmax: time to reach peak plasma concentra-
tion; AUClast: area under the (zero moment) curve from time 0 to the last de-
tectable concentration, MRT: mean residence time; T1/2λz: terminal half-life.
intestine of monogastric animals (Faulkner et al., 1972).
The pharmacokinetic parameters of PYR in horses and donkeys are
shown in Table 5. The pharmaceutical formulation of anthelmintic
drugs may affect their oral bioavailability, which depends on the rate
and extent of absorption of the drug from the gastrointestinal tract into
the bloodstream. In donkeys, pharmacokinetic results have indicated
that the paste formulation differed significantly from the granule for-
mulation of PYR at the same dose rate after oral administration
(Gokbulut et al., 2014). The plasma concentrations of PYR were much
lower following administration of the paste formulation than those
observed following granule administration. After oral administration,
Cmax (0.09 μg/mL) was significantly lower (P < 0.01) and AUC (2.65
μg.h/kg) smaller (P < 0.01) for PYR paste than PYR granule (Cmax:
0.21 μg/mL, AUC: 5.60 μg h/kg) given at the same dose rates (6.94 mg/
kg BW). It is likely that the poorer dissolution of the paste formulation
reduces its absorption compared with the granule formulation in don-
keys (Gokbulut et al., 2014).
The pharmacokinetic properties of PYR in donkeys differed sub-
stantially from those previously reported by Gokbulut et al. (2001a) in
horses using the same formulation and administration route. In horses,
PYR paste was administered at a dose of 13.3 mg/kg BW, whereas in
donkeys, it was administered at a dose of 6.94 mg/kg BW. The lower
concentrations and shorter MRT of PYR in the plasma of horses reflect
lower bioavailability and shorter persistence compared with donkeys.
After correction for dose, assuming proportionality, Cmax (0.045 μg/
mL), AUC (0.53 μg h/mL) and MRT (11.99 h) values in horses were
much lower than those observed in donkeys (Cmax: 0.09 μg/mL, AUC:
2.65 μg h/mL and MRT: 24.80 h). The gastrointestinal passage rate of
digesta is affected by alteration in the quality and quantity of the feed
consumed and this could confer variable absorption time and therefore
bioavailability of drugs administered orally. It has been shown that
variations in the quality (McKellar et al., 1993a; Gokbulut et al., 2007)
and quantity (Lifschitz et al., 1997; McKellar et al., 2002; Gokbulut
et al., 2010a) of diet could affect the bioavailability of anthelmintics in
different animal species. Differences between studies referred to in
Table 5 may be associated with diet type in donkeys compared with
horses. In the studies by Gokbulut et al. (2001a, 2014), donkeys were
kept indoors and fed hay-based diet whereas, horses were yarded for
the period during and immediately (4 h) after drug administration and
were then returned to a grass paddock. The grass-based diet probably
decreased gut transit time for food, causing a decrease in the bioa-
vailability of PYR in horses compared with those in donkeys. Moreover,
anatomic features influence the passage of digesta, and the bioavail-
ability and pharmacokinetics of anthelmintics may be affected by dif-
ferent gut transit time in animal species (McKellar and Scott, 1990).
Parasitism could have had an effect since donkeys were naturally in-
fected with intestinal parasites and such infections may have modest
effects on the absorption of anthelmintics (McKellar et al., 1991), un-
fortunately the parasitological status of the horses or the history of
39
Veterinary Parasitology 261 (2018) 27–52
anthelmintic treatment in horses was unknown.
These studies demonstrate limited absorption of PYR following oral
administration in horses and donkeys and it seems likely that a sub-
stantial component of its dynamic effect will be associated with PYR
retained in the gastrointestinal tract where the adult stages of most
parasitic nematodes reside. Any substantial effect of PYR on faecal in-
vertebrates is not known, however, it is apparent that faeces from
treated horses and donkeys will have high concentrations of PYR for at
least 120 h for donkeys (Gokbulut et al., 2014) and 48 h for horses
(Gokbulut et al., 2001a).
4. Macrocyclic lactones (avermectins and milbemycins) in equine
species
Macrocyclic lactones (MLs, avermectins and milbemycins or en-
dectosides) comprise a series of natural and semisynthetic molecules,
including ivermectin (IVM), abamectin (ABM), moxidectin (MXD),
doramectin (DRM), eprinomectin (EPM), selamectin (SLM) and milbe-
mycin oxime, which have some similar physicochemical properties, and
antiparasitic activity at very low dosage rates based on a common mode
of action (Lanusse and Prichard, 1993). They are highly effective
against nematode and ectoparasitic arthropods in human and different
animal species. Therefore, MLs have been renamed as “endectocides”
since they are unique drugs effective against both endo- and ectopar-
asites. However, these compounds are not effective against trematodes
or cestodes. Currently, IVM, MXD, DRM and ABM are licensed by some
authorities for use in horses for the treatment of endo- and ecto-para-
sites. They are usually administered orally as a paste or gel formulation,
although a liquid oral formulation of IVM for horses is also available in
the market.
The milbemycins were discovered in 1973 as acaricidal and in-
secticidal compounds for crop protection (Takiguchi et al., 1980).
However, the full potential of these chemical groups was not realized
until the acaricidal, insecticidal and nematocidal activity of the aver-
mectins was documented in 1975 (Egerton et al., 1979). This discovery
started a new era in the treatment of endo- and ecto-parasitic infections
in animal and human medicine. The excellent microfilaricidal activity
of IVM against Dirofilaria immitis infections was discovered in dogs
during anthelmintic development studies (Blair and Campbell, 1979)
and Onchocerca cervicalis infections in horses (Herd and Donham,
1983). Ivermectin was firstly introduced commercially as an animal
endectocide in 1981 in France (Shoop et al., 1995) and within 5 years,
it became the most popular anthelmintic worldwide. It was shown that
avermectins had good activity against microfilaria of Onchocerca vol-
vulus, and were well tolerated in man (Aziz et al., 1982). Abamectin was
introduced commercially as a veterinary endectoside in 1985 in Aus-
tralia (Tahir et al., 1986). Moxidectin was developed in the USA and
approved for marketing in Argentina in 1989 (Campbell, 2012). It has
been commercialized for use in cattle as a subcutaneous injectable so-
lution (1%) and pour-on preparation (0.5%), in sheep as an oral drench
(0.1%) and in horses as an oral gel (2%) (at 0.4 mg/kg therapeutic dose
level). An injectable formulation of MXD for equine species was de-
veloped and its anthelmintic activity was evaluated but not marketed
(Lyons et al., 1992). Milbemycin oxime has been licensed in the USA for
use in dogs against adult Ancylostoma caninum as a therapeutic agent
and against D. immitis as a prophylactic drug since 1990 (Bowman et al.,
1990). Doramectin was developed in the UK and first marketed in 1993
in Brazil and South Africa (Vercruysse, 1993). Doramectin formulation
was developed with oil vehicles to enhance the persistence of efficacy in
treated animals (Conder and Baker, 2002). Like other avermectins, it
has therapeutic activity against gastrointestinal nematodes and ar-
thropod parasites (Conder and Campbell, 1995). Eprinomectin, the
most recently introduced avermectin, is a semi-synthetic avermectin. It
has been demonstrated that EPM has 2–3 times higher anthelmintic
efficacy compared to that of IVM in titration trials (Shoop et al., 1996b).
Pour-on formulations for topical administration and injectable
C. Gokbulut, Q.A. McKellar
formulations for subcutaneous injection of EPM were licensed and
made available in the market for use in cattle and deer only.
Macrocyclic lactones are widely used in horses for the treatment of
gastrointestinal nematodes and ectoparasitic infections. The physico-
chemical properties including high lipophilicity and stability allow a
wide flexibility on their pharmaceutic formulations. There are a variety
of the formulations for the MLs, including formulations which combine
the different member MLs with other anthelmintically active in-
gredients to broaden the spectrum of activity of the combination.
Ivermectin was first marketed for horses as a micellar formulation
containing 20 mg of IVM per millilitre of sterile aqueous solution (2%)
for intramuscular injection. After parenteral administration, rare ad-
verse reactions including Clostridium spp. infections and anaphylaxis
were observed, and these undesirable effects were responsible for the
withdrawal of the parenteral preparation of IVM for use in the horse in
1984 (Campbell et al., 1989). An oral paste formulation of IVM (1.87%)
in titanium dioxide and propylene glycol is now available in graduated
delivery syringes of which each part is designed to administer sufficient
IVM (at 200 μg/kg) for 100 kg of body weight. A liquid formulation of
IVM is also marketed for administration by nasogastric intubation in
some countries. Moxidectin oral gel formulation (2%) is commercially
available for antiparasitic treatment of horses. Another MXD (2%) oral
gel formulation combined with praziquantel (12.5%) is available to
provide activity against cestodes (Cobb and Boeckh, 2009). Abamectin
(1.87%) paste in combination with praziquantel (14.03%) and DRM
(1.75%) oral gel formulations have been developed and are available in
some markets for treatment of endo- and ecto-parasitic infections in
horses.
4.1. Chemistry and metabolism
The chemical structures of MLs are closely related and have a 16-
membered ML ring, with a disaccharide substitution at C-13 (Fig. 4).
The major structural difference between the two groups is a bisolean-
drosyloxy substituent found at the C-13 position of the macrolide ring
of the avermectins whereas that position is unsubstituted in milbemy-
cins. The sugar moiety at C-13 together with the hydroxy group at C-5
may determine anthelmintic and insecticidal activity (Jackson, 1989).
Avermectins are derived from the mycelia of Streptomyces avermitilis
and milbemycins are produced from fermentation of Streptomyces hy-
groscopicus and Streptomyces cyanegriseus. Fermentation of S. avermitilis
produces eight different components and they are named avermectin
A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. The A-components have a
methoxy group at the 5-position, whereas the B-components have a
hydroxy group; the 1-components have a double bond between the 22-
and 23-position, whereas the 2-components have a single bond with a
hydroxy group at the 23-position; and a-components have a secondary
butyl side chain at the 25-position, whereas the B-components have an
isopropyl substituent at the 25-position. Doramectin is structurally si-
milar to avermectin A1a but with cyclohexyl and methylpropyl sub-
stituents at Carbon 25. More radical alteration at C-25 has been
achieved by mutational biosynthesis (Dutton et al., 1991) and the 25 –
cyclohexyl derivative (DRM) has a longer elimination half-life and
slower clearance than unsubstituted dihydro avermectin B1a (the major
component of IVM) (Goudie et al., 1993). Abamectin (avermectin B1)
contains at least 80% of avermectin B1a and not more than 20% aver-
mectin B1b whereas, IVM, contains at least 80% of 22–23 dihy-
droavermectin B1a and less than 20% of the 22–23 dihydroavermectin
B1b. Eprinomectin (4″-epi-acetylamino-4″-deoxy-avermectin B1) is a
semi-synthetic avermectin and is derived from avermectin B1 with
modified terminal oleandrose moiety called 4″-epiacetylamino-4″-
deoxy-avermectin B1. Chemically, EPM is a mixture of two homologs,
EPM B1b and EPM B1a in a 9:1 ratio. The difference between the two
groups is a single methylene group at C25-position (Fig. 4). Substitution
of the C-4″ hydroxy group with acyl, amino or thio groups improve the
solubility and disposition of avermectins and this feature has been
40
Veterinary Parasitology 261 (2018) 27–52
embraced by the epi-acetyl amino substitution in EPM which retains/
enhances the potency and spectrum of activity of this avermectin yet
enhancing its absorption from skin and conferring a very low milk ex-
cretion rate permitting its use in dairy cows (Shoop et al., 1996a).
The milbemycins including MXD, are not only different from the
avermectins in lacking sugar groups in the 13-position, they also differ
from the avermectin aglycones by being protonated at this position in
contrast to the avermectin aglycones which are hydroxylated at this
position. Milbemycins have an ethyl or a methyl at the 25-position and
differ from one to another by their substituents in the 5- and 25-posi-
tion. Moxidectin has a substituted olefinic side chain at the 25-position
and methoxime moiety at the 23-position which are both characteristics
specific for this drug and not found in other milbemycins or avermec-
tins.
Macrocyclic Lactones are highly lipophilic substances and dissolve
in most organic solvents, such as chloroform, acetone, toluene and
methylene chloride. Their solubility in water is very low
(0.006–0.009 mg/l) (Fisher and Mrozik, 1989). Moxidectin has a lower
molecular weight (639.8 kDa) and higher water solubility (4.3 mg/l)
than ABM and IVM (mol. wt. ∼870 kDa) (Lanusse and Prichard, 1993).
In contrast with this, it was reported that MXD was 100 times more
lipophilic than IVM (Hayes, 1994). The water solubility and lipophili-
city of MXD are unusual for a drug since increased water solubility is
usually directly associated with decreased lipophilicity. Macrocyclic
Lactones do not contain strongly acidic or basic functional groups and
pH partitioning is not a major feature of their kinetic characteristics.
These physicochemical differences may affect pharmacokinetic beha-
viour, development of drug resistance and parasite uptake mechanism
(Lanusse and Prichard, 1993). All members of the MLs are thought to be
highly protein bound in plasma however their lipophilicity and asso-
ciation with circulating lipoproteins may be important determinants in
their exchange between tissue and bloodstream (Lespine et al., 2009).
Metabolic enzymes in nematodes (Alvinerie et al., 2001) and in
mammals (Chiu et al., 1987) can metabolize MLs. Cytochrome P450
3 A4 is the predominant isoform, which is primarily responsible for the
metabolism of avermectins, by liver microsomes in rats (Zeng et al.,
1997) and humans (Zeng et al., 1998). However, metabolism is not a
common pathway for the elimination of these compounds which are
primarily eliminated in faeces, with less than 2% of the total dose being
excreted in urine (Chiu et al., 1990). Liver and fat are two main tissue
sites of IVM biotransformation. The unchanged parent compound is the
main liver residue in cattle, sheep and rats treated with IVM and the
major liver metabolite is a 24-hydroxy-methyl-H2-B1a and H2-B1b (Chiu
et al., 1987). The monosaccharide and aglycone forms of these meta-
bolites were also identified in the liver. The major excretion routes of
avermectins are bile and faeces in all animal species studied (Chiu and
Lu, 1989). Ivermectin has been shown to be excreted in high con-
centrations in the bile of ruminants (Bogan and McKellar, 1988).
Considerable amounts of IVM are also excreted via the mammary gland
in animals during the milking period. N-deacetylation of AAB1 has been
shown to be the primary metabolic route of EPM in rats (Zeng and
Andrew, 1999). C29-30- and C14-mono-hydroxy-methyl derivatives are
the main metabolic products of MXD (Zulalian et al., 1994) produced
by the cytochrome enzymes, P450 3 A and P450 2B (Dupuy et al.,
2001b). It has been reported that the absorption, distribution in tissues,
metabolism, and elimination of MXD in the horse were similar to those
reported for cattle, sheep, and rat (Afzal et al., 1997). Although minor
metabolites were observed, parent MXD molecule was the principal
excretory component and MXD was eliminated from the body mainly
via biliary excretion (Afzal et al., 1997) and probably intestinal excre-
tion and subsequently voided with faeces.
4.2. Efficacy and spectra of activity
Ivermectin, MXD, DRM and ABM which are licensed MLs for use in
horses, are highly effective against bots, lungworms, thread worms,
C. Gokbulut, Q.A. McKellar
Fig. 4. Chemical structures of MLs (endectocides).
cutaneous onchocerciasis and ectoparasites. However, the major an-
thelmintic activities of MLs against common gastrointestinal nematodes
in equine species are shown in Table 3. Ivermectin, 0.2 mg/kg body
weight given orally, is highly active against adult and third-stage pul-
monary larvae (L3) of P. equorum (French et al., 1988) but has variable
activity against fourth-stage (L4) intestinal larvae (Campbell et al.,
1989) in horses. It is more than 90% effective against adult cyathos-
tomins but has very little or no activity against hypobiotic early third-
stage or mucosal late third-or fourth stage larvae (Eysker et al., 1992).
An efficacy study of IVM for ascarids indicated that the oral formulation
of IVM is 90–100% effective against pulmonary and small intestinal
stages in foals and weanlings (Austin et al., 1991). Ivermectin is highly
41
Veterinary Parasitology 261 (2018) 27–52
effective against adult Strongylus spp., arterial stages of S. vulgaris and
migratory S. edentatus, (Klei et al., 1984; Slocombe and Mccraw, 1984),
S. westeri (Ryan and Best, 1985) and D. arnfieldi (Britt and Preston,
1985). In ponies, IVM is fully effective against oral and gastric stages of
Gasterophilus spp. after oral administration at 0.2 mg/kg body weight
(Bello, 1989). The previous studies indicated that IVM and MXD were
highly effective against adult cyathostomins but less effective against
immatures (L4) in the intestinal mucosa (Lyons et al., 2010).
It has been shown that MXD has excellent activity against equine
nematodes (Lyons et al., 1992; DiPietro et al., 1997; Dorchies et al.,
1998b). It has higher activity than IVM against tissue strongyle larvae
when given at an equal oral dose (DiPietro et al., 1997). In MXD treated
C. Gokbulut, Q.A. McKellar
horses it was reported that strongyle mean egg per gram counts (EPG)
remained low for longer than in IVM treated horses (Boersema et al.,
1998). The greater lipid solubility of MXD as compared to IVM may
explain its increased activity against these parasites (Hayes, 1994;
Zulalian et al., 1994). The activity of MXD, given orally at 0.4 mg/kg,
was 100% effective against T. axei, Triodontophorus spp., O. equi L5 and
cyathostomins (adult and L5); 99% against O. equi L4 and 92% against S.
edentatus L5 and G. intestinalis (Dorchies et al., 1998b). One hundred per
cent reduction of strongyle Faecal Egg Counts (FECs) was reported after
MXD treatment (Jacobs et al., 1995; Dorchies et al., 1998a). It was
shown that IVM and MXD were equally effective in reducing P. equorum
EPG (egg per gram counts) (DiPietro et al., 1997). After oral adminis-
tration, MXD and IVM were fully effective in the control of Onchocerca
cervicalis microfilariae in horses (Mancebo et al., 1997). Moreover,
MXD was highly effective against S. vulgaris (faecal egg count reduction
range, 99.9–100%) for 2 weeks after treatment (Tzelos et al., 2017).
Ivermectin and MXD provided acceptable efficacy (Lester et al., 2013;
Relf et al., 2014; Stratford et al., 2014); however, strongyle EPG counts
results suggest that both drugs are less effective compared to the find-
ings of previous studies done when these compounds were first mar-
keted (Lyons et al., 2011; Relf et al., 2014). Doramectin displayed a
high efficacy of ≥96% in terms of reduction of faecal egg counts in
horses with strongylidae infections and egg reappearance period was 10
weeks after intramuscular administration at a dose of 0.2 mg/kg (Cirak
et al., 2007). Doramectin was highly efficacious (99.6%) against
strongyles (Strongylidae and Cyathostomins) and strongyle eggs re-
appeared 2 months after subcutaneous administration at a dose of
0.2 mg/kg BW in horses (Prokulewicz et al., 2014). Abamectin was
highly effective against gastrointestinal parasites including Strongylus
spp. Oxyuris equi and Parascaris equorum following subcutaneous ad-
ministration at a dose of 0.2 mg/kg BW in horses (Mahfooz et al., 2008).
In donkeys, IVM was highly effective (96%) against strongyloidiasis
in terms of reduction of EPG following subcutaneous administration at
a dose of 0.2 mg/kg BW (Binev et al., 2005). In addition, it has been
reported that IVM was 100% effective against T. axei, P. equorum, O.
equi, Strongylus spp. and cyathostomins, however, it had moderate ef-
ficacy (62.71%) against larvae found in the cranial mesenteric artery
aneurisms after oral treatment in donkeys (Imam et al., 2010). Iver-
mectin was also effective in the treatment of psoroptic mange in don-
keys following subcutaneous administration at a dose of 0.2 mg/kg BW
(Abusamra et al., 1987) and had an efficacy of 96% in terms of re-
duction of faecal egg counts in donkeys with strongylidae infections
after subcutaneous administration at a dose of 0.2 mg/kg (Binev et al.,
2005). The anthelmintic activity of pour-on EPM against the lungworm
D. arnfieldi was 100% at a dose of 0.5 mg/kg BW in donkeys (Veneziano
et al., 2011).
It has been reported that MXD and IVM were 100% effective against
chorioptic and psoroptic mite infestations following oral doses of
0.4 mg/kg and 0.2 mg/kg BW, respectively and complete clinical re-
covery were observed within 2 weeks in both drug treatment groups
(Osman et al., 2006). Ivermectin and DRM were highly effective against
chorioptic mange in horses and donkeys following two oral doses of
either drug given 14 days apart at a dose of 0.2 mg/kg BW (Kotb and
Abdel-Rady, 2013). Horses with psoroptic manage were effectively
cured with four pour-on EPM administrations with a one-week-intervals
at a dose of 0.5 mg/kg BW (Ural et al., 2008). In addition, five donkeys
with psoroptic mange were successfully treated with subcutaneous IVM
injection at a dose of 0.2 mg/kg BW (Abusamra et al., 1987). In contrast
to these reports, horses with chorioptic mange were not cured with oral
IVM paste at a dose rate of 0.1 mg/kg daily for 10 days or two doses of
0.2 mg/kg given two weeks apart (Littlewood et al., 1995).
4.3. Mode of action
Although the mechanism of action of MLs anthelmintics is not fully
understood, it is likely that it is common to the group. In Ascaris
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Veterinary Parasitology 261 (2018) 27–52
lumbricoides, avermectins reduced inhibitory neuromuscular transmis-
sion by a gamma-aminobutyric acid (GABA)-mediated mechanism at a
concentration of 5 × 10−6 M (Kass et al., 1984). At this concentration,
avermectins were thought to induce presynaptic GABA release or
function as GABA agonists. At lower concentrations (2 × 10-12 M),
avermectins open GABA-independent chloride channels in A. suum
muscle membranes and surprisingly, avermectins were shown to be
antagonistic to GABA-gated chloride ion channels at concentrations >
10−8 M (Martin and Pennington, 1989).
Although early reports suggested that the chloride channels were
associated with gamma aminobutyric acid (GABA) receptors (Turner
and Schaeffer, 1989), more recent evidence indicates that there is no
GABA-gated Cl− channel association (Geary et al., 1992; Martin, 1997).
Expression cloning experiments using Xenopus oocytes have suggested
an action of avermectins on avermectin-sensitive glutamate-gated Cl−
(GluCl) channels (Cully et al., 1994) and avermectins and milbemycin
mediate their nematocidal effects on Caenorhabditis elegans via inter-
action with a common receptor molecule at glutamate-gated channels
(Arena et al., 1995). Molecular studies showed that the Glu-Cl β-subunit
of the glutamate channel was expressed in the pharyngeal muscle of C.
elegans (Laughton et al., 1995) and it was demonstrated that aver-
mectin-sensitive glutamate-gated chloride channels were present on the
pharyngeal muscle of A. suum by using a microelectrode current clamp
technique (Martin, 1996). Thus, while at high concentrations, aver-
mectins open the GABA-gated ion channel directly, at lower con-
centrations, they potentiate the effect of glutamate (Martin, 1997).
Ivermectin has been shown to have excellent binding affinity for a
P-glycoprotein (P-gp) which acts as a transmembrane efflux pump
(Didier and Loor, 1996; Pouliot et al., 1997) and that the high tolerance
of mammals to IVM is abolished if the blood-brain barrier P-gp is de-
leted (Schinkel et al., 1994). Thus, MLs probably have more than one
mechanism of action against nematodes (Martin, 1997).
In ectoparasites (Shistocerca gregaria) it has been reported that IVM
interacted with both a GABA receptor-Cl− ion channel (10-10 M) in a
reversible dose-dependent fashion and with GABA-insensitive neurones,
where an irreversible increase in Cl- conductance was noted at 10-10 M
(Duce and Scott, 1985). In contrast, in the ectoparasite, Periplaneta
americans, avermectin B1a had no effect on GABA-independent neuronal
conductance (Mellin et al., 1983), although avermectin-sensitive GABA
binding sites have been identified in insect nerve cord (Lummis and
Sattelle, 1985).
The selective therapeutic effects of MLs may be explained by an
action on a Glu Cl− ion-channel, present in nematodes and ectopar-
asites, but not in mammals (Martin, 1997). In addition, the pharma-
cokinetic properties of MLs may determine their selective activity in
nematodes (reviewed by McKellar and Benchaoui, 1996). Ivermectin
distributes poorly into the brain of mammalian species (Chiu and Lu,
1989) and the affinity of IVM for specific binding sites in C. elegans is
much higher (100-fold) than in rat brain (Turner and Schaeffer, 1989).
The effects of avermectins are variable on different nematode spe-
cies. While a slow rigid paralysis was observed in the free-living ne-
matode, C. elegans, a flaccid paralysis was reported following injection
into A. suum (Turner and Schaeffer, 1989). It was also shown that
avermectins reduced the fecundity (amount of eggs in the uterus) of
Cooperia curticei by 99% (McKellar et al., 1988) and the reproductive
potential of Dermacentor albipictus and Amblyomma americanum
by > 96% (Wilkins et al., 1981).
4.4. Safety and toxicity
Avermectins and milbemycins have a substantial margin of safety
and high therapeutic indices when compared with other anthelmintic
xenobiotics. Nevertheless, since GABA is a neurotransmitter limited to
the central nervous system in mammals, neurotoxicity may occur when
MLs are administered at high doses. Neurotoxicity characterised by
ataxia, tremors and coma was identified (Lankas and Gordon, 1989).
C. Gokbulut, Q.A. McKellar Veterinary Parasitology 261 (2018) 27–52

Table 6
Pharmacokinetic parameters of endectocides in equine species.
Pharmacokinetic parameters References

Species MLs Route Dose Cmax Tmax AUC T1/2 MRT Vdss Cl
(μg/kg) (ng/mL) (h) (ng.h/mL) (h) (h) L/kg (L/h/kg)

Horse IVM IV 0.2 – – 8226.5 138.72 147.12 3.65 15.12 Gokbulut et al. (2010b)
SC 0.2 60.7 80 13209.6 88.2 114.7 – – Marriner et al. (1987)
IM 0.2 31.4 84 7245.6 108.5 206.4 – – Perez et al. (2003)
IM 0.2 25.9 67.2 8328 219.84 194.4 – – Saumell et al. (2017)
T 0.5 4.3 103.9 1438.3 172.3 283.2 – – Gokbulut et al. (2010b)
PO 0.2 46.3 7.0 2646 – – – – Scott (1997)
PO 0.2 25.8 5.5 1941.8 88.1 117.6 – – Gokbulut et al. (2016b)
PO 0.2 82.3 3.1 4821.6 66.3 – – – Marriner et al. (1987)
PO 0.2 21.4 7.9 1106.4 51.6 55.2 – – Gokbulut et al. (2001b)
PO 0.2 44.0 2.2 3184 102 114.7 – – Perez et al. (1999)
PO 0.2 51.3 3.6 3290.4 69.4 100.8 – – Perez et al. (2003)
PO 0.2 61.3 4.1 3959 156.7 176.2 – – Gokbulut et al. (2010b)
PO (Paste) 0.2 30.1 7.92 2736 131.52 122.4 – – Saumell et al. (2017)
PO (Sol.) 0.2 33.7 12 3312 151.68 124.8 – –
DRM IM 0.2 33.3 69.6 9446.4 223.2 319.2 – – Perez et al. (2010)
PO 0.2 51.6 4.8 4286.4 124.3 185.3 – –
PO 0.2 21.3 8.0 1279.2 93.8 72.0 – – Gokbulut et al. (2001b)
MXD IV 0.4 – – 11,400.0 81.0 92.3 4.14 36.0 Afzal et al. (1997)
PO 0.4 102.0 8.0 4550 82 – – –
PO 0.2 30.1 7.9 2227.0 534.5 420.0 – – Gokbulut et al. (2001b)
PO 0.4 70.4 8.9 8726.0 554.6 442.1 – – Perez et al. (1999)
ABM PO 0.2 34.82 36.0 3137.0 134.4 92.4 – – Echeverria et al. (2001)
EPM T 0.5 17.7 43.2 424.6 32.9 70.3 – – Gokbulut et al. (2016b)
Donkey IVM PO 0.2 23.6 24 2863.2 177.6 156.0 – – Gokbulut et al. (2005)
PO 0.3 43.2 8.0 1811 – – – – Scott (1997)
DRM PO 0.2 33.9 24.0 5493.6 266.4 218.4 – – Gokbulut et al. (2005)
EPM T 0.5 14.2 81.1 3106.4 151.9 214.8 – – Gokbulut et al. (2013)
T 0.5 6.1 113.0 1761.4 113.44 215.5 – – Gokbulut et al. (2011)

Cmax: peak plasma concentration; Tmax: time to reach peak plasma concentration; AUClast: area under the (zero moment) curve from time 0 to the last detectable
concentration, MRT: mean residence time; T1/2λz: terminal half-life, AUMC: area under the first moment curve, Vdss: Volume of distribution at steady state, Cl:
Clearance.

Avermectins cause the release of endogenous GABA from cerebral
cortex synaptosomes of the rat (Pong et al., 1980) and bind to two
different sites in the GABA-gated chloride channel, activating the
channel on binding to the high-affinity site and blocking it on further
binding to the low-affinity site in rat cerebellar granule neurones
(Huang and Casida, 1997). The specific avermectin-binding sites may
be blocked by GABA and GABA agonists (Drexler and Sieghart, 1984).
Deficiency of P-gp, a transmembrane glycoprotein associated with
multidrug resistance (Goldstein et al., 1989), was shown in the in-
testinal epithelium and brain capillary endothelium in CF-1 mice which
were 100-fold more sensitive to avermectin neurotoxicity than other
species and normal mice (Lankas et al., 1997).
The toxicity of MLs has been correlated with their disposition in
susceptible species and breeds of animals (McKellar, 1997a,b). The
distribution of IVM is restricted by the blood-brain barrier from the
central nervous system of mammalian species (Chiu and Lu, 1989). The
central nervous system of neonatal rats is more sensitive to toxicity than
that of adult rats due to the immature blood-brain barrier (Lankas and
Gordon, 1989). It has been shown that IVM was pumped as an efflux by
P-gp in the blood-brain barrier of mice and this may prevent the ac-
cumulation of IVM in normally tolerant animals (Schinkel et al., 1994,
1996). It is thought that the toxicity of MLs occurs due to inadequate
and deficient P-gp mediated drug transport in the blood–brain barrier.
(Lespine et al., 2006, 2007). P-glycoproteins act as transport proteins
able to carry some drugs, including MLs, across cell membranes. Over-
or under-expression of P-gp can lead to accumulation or depletion of
these drugs within cells. Moreover, there is a structure-affinity relation
for P-gp mediated drug transport of MLs and MXD is a poorer substrate
for P-gp, compared to other MLs, such as IVM and SLM (Lespine et al.,
2007). Although mammalian species have different sensitivity, similar
signs of acute MLs toxicity, such as ataxia, tremors and coma are ob-
served in most species (Lankas and Gordon, 1989). The oral lethal doses
of IVM for 50% of a population (LD50) are 25, 50 and 80 mg/kg in
mouse, rat and dog (beagle), respectively (Fisher and Mrozik, 1992).
Toxicity of MLs is rare in equine species. A few sporadic IVM and
MXD toxicosis in equine species have been reported in the literature
and most of them are related to substantial over-dose administration. It
has been reported that a four-year-old thoroughbred gelding collapsed
following the intravenous administration of 10 ml of a cattle formula-
tion of IVM (1.0% w/v) (Burrough, 1986). The CNS symptoms such as
tremors, especially of the neck and forelimb, and periodic nystagmus
observed in this horse which became comatose were similar to those
reported in collies affected by IVM. In addition, IVM toxicosis was re-
ported in three adult horses following administration of single dose
paste (1.87%) formulation (Swor et al., 2009). Clinically, bilateral
mydriasis, decreased pupillary light reflexes, and absent menace re-
flexes were observed in these animals. A high concentration of IVM was
detected in the brain tissue at post-mortem examination of one of the
affected horses which were euthanized. An over-dose of IVM was ac-
cidentally administered orally to a 3-month-old zebra (Hautekeete
et al., 1998) and in a separate instance to a 9-week-old miniature mule
foal; similar clinical CNS symptoms occurred as those reported in
horses, including temporary blindness (Plummer et al., 2006). Mox-
idectin intoxications with CNS symptoms including coma, dyspnoea,
depression, ataxia, tremors, seizures, or weakness have been also re-
ported in equine species following oral over-dose administrations
(Johnson et al., 1999; Khan et al., 2002).
In horses, IVM at more than three times the therapeutic dose ad-
ministration and MXD at the therapeutic dose were not embryotoxic
and produced no adverse clinical abnormality in pregnant mares and
new-born foals (Campbell and Benz, 1984; Mckissick et al., 1987).
Ivermectin did not adversely affect the fertility of mares or the orga-
nogenesis of their developing foals following oral treatment at a
0.6 mg/kg dose rate (therapeutic dose x 3) (Mckissick et al., 1987).

43
C. Gokbulut, Q.A. McKellar
Single oral IVM at doses of 0.2 or 0.6 mg/kg did not affect the sexual
behaviour of stallions or quality of their semen (Janett et al., 2001).
Genotoxicity and carcinogenicity studies indicated that ABM and IVM
had no genotoxic activity and no carcinogenic potential, respectively
(Lankas and Gordon, 1989).
4.5. Pharmacokinetics
Macrocyclic lactones are extremely lipophilic compounds that are
extensively distributed from the bloodstream to different tissues and
slowly eliminated from body compartments, especially liver and fat
(Zulalian et al., 1994), and for this reason, large volumes of distribution
and longer persistence in the animals treated are observed for these
drugs compared to the other classes of anthelmintics. The pharmaco-
kinetic dispositions of MLs are significantly affected by route of ad-
ministration, the formulation of the drug, and interspecies and inter-
individual variation (reviewed by McKellar and Benchaoui, 1996;
McKellar and Gokbulut, 2012). The studies on the pharmacokinetic
dispositions of MLs have been well documented in the last few years
and are summarized in Table 6. As in other animal species, the phar-
macokinetic dispositions of IVM has been investigated more extensively
compared to that of the other members of the MLs since IVM was the
first licensed and the most widely used endectocide in equine species.
In horses, the kinetic results for IVM obtained from eight studies
(Table 10) display great variations (Cmax: 45.31 ± 20.16 ng/mL, tmax:
5.17 ± 2.24 h, AUC: 2960.65 ± 1149.18 ng.h/mL, T1/2:
95.06 ± 37.86 h, MRT: 114.48 ± 38.94 h following oral administra-
tion at the same dose rate. The reasons for these differences between
the studies are unknown but may in part be due to differences in
methodology. It is unlikely that formulation differences could be re-
sponsible since all studies used the paste formulation of IVM. Feeding
type or fasting could have caused differences in drug absorption, al-
though feeding is not considered to cause such substantive differences
in the oral absorption of anthelmintics in horses as it does in ruminants
(Ali and Hennessy, 1996; Gokbulut et al., 2007) and dogs (McKellar
et al., 1993a). In some of the reported studies, the horses were kept
indoors and fed a hay-based diet whereas, in other studies, the horses
were yarded for the period during and immediately after drug admin-
istration and were then returned to a grass paddock (Gokbulut et al.,
2001b). One of the most likely factors affecting the pharmacokinetics of
IVM was the breed and size of the animals used. Perez et al. (1999) used
Chilean criollo horses weighing 380–496 kg whereas a mixed group of
thoroughbreds weighing between 510–610 kg were administered IVM
in the study by Gokbulut et al. (2001b). Parasitic status of animals
could have had an effect, since the horses used by Perez et al. (1999)
were known to be infected with gastrointestinal parasites and such
infections may have modest effects on absorption of anthelmintics
(McKellar et al., 1991), unfortunately, the parasitological status of the
horses in most of these studies was unknown.
Moxidectin is much more lipophilic than the avermectins including
IVM and DRM and remains longer in the treated animals which explains
the higher AUC and longer MRT which have been demonstrated in
ruminant species (Zulalian et al., 1994; Alvinerie et al., 1998; Carceles
et al., 2001) and following subcutaneous injection and oral adminis-
tration in horses (Gokbulut et al., 2001b). However, the kinetic para-
meters observed after intravenous administrations of IVM at a dose of
0.2 mg/kg BW (Gokbulut et al., 2010b) and MXD (at a dose of 0.4 mg/
kg BW) (Afzal et al., 1997) are not in agreement with these findings in
horses. Although, the Vdss and oral bioavailability values are similar for
IVM (Vdss:3.65 L/kg and Foral: 48%) and MXD (4.14 L/kg and Foral:
40%), the AUC (8226.5 ng.h/mL), T1/2 (138.72 h) and MRT (147.12 h)
values of IVM were much greater than those observed after MXD ad-
ministration (AUC: 5700 ng.h/mL, dose corrected (0.2 mg/kg BW) as-
suming proportionality, T1/2: 81.0 h and MRT: 92.3 h) in horses. The
reason for these differences in the kinetic dispositions of IVM and MXD
between oral and intravenous administrations is unclear but it might in
44
Veterinary Parasitology 261 (2018) 27–52
part be due to the differences in the methodology of the two different
intravenous studies. Male horses weighing 200–400 kg were used in the
MXD study (Afzal et al., 1997) whereas female horses weighing
510–600 kg were used in the IVM study (Gokbulut et al., 2010b). It has
been observed that body weight and gender of the animals significantly
affect the plasma dispositions of MLs (McKellar and Gokbulut, 2012).
The aqueous solubility of an active molecule may affect its bioa-
vailability, which depends on the rate and extent of absorption of the
drug from the site of application into the bloodstream (Baggot and
McKellar, 1994). Although the antiparasitic spectrum and efficacy of
the different ML molecules are similar, different physicochemical
properties of these drugs may account for differences in kinetic beha-
viour, potency and persistence of their antiparasitic activity (Lifschitz
et al., 2004) and in compatibility with excipients for formulation. The
vehicle in the pharmaceutical formulations of endectocides may play an
important role in their absorption from the site of administration and
bioavailability (Lo et al., 1985). In horses, it was demonstrated that
time to the reach the peak plasma concentration (4–5 h) for the liquid
formulation of IVM was much shorter compared to that for the paste
formulation (15 h) following oral administrations at a dose of 0.2 mg/
kg BW. In addition, after treatment of horses with a liquid form of IVM
via nasogastric tube, 20% higher bioavailability was obtained than for
the oral paste form. Nevertheless, the anthelmintic activity of both IVM
formulations was similar when measured by reduced faecal egg count
(Asquith and Kivipelto, 1987; Asquith et al., 1988). In contrast with this
finding, recently, it has been reported that although, the other kinetic
parameters were similar, oral administration of a propylene glycol-
based solution of IVM (2%) resulted in a later peak plasma concentra-
tion (12 h) compared to the paste form (7.72 h) in horses (Saumell
et al., 2017). The differences between these two studies are probably
related to the different formulations of the oral solutions or the feeding
regime or body conditions of animals in each study.
Limited information is available in the literature on the pharma-
cokinetics of MLs after parenteral administration in horses, since the
parenteral formulation of IVM has been shown to cause rare adverse
reactions including Clostridium spp. infection and anaphylaxis
(Campbell and Benz, 1984) and the parental formulation was with-
drawn in 1984 after a short period on the market (Lyons and Tolliver,
2012). Although no authorised MLs are now available for parenteral
administration, the plasma dispositions of IVM and DRM have been
investigated in horses after subcutaneous or intramuscular off-label
administration of the formulation licensed for use in cattle (Marriner
et al., 1987; Perez et al., 2003, 2010; Saumell et al., 2017). The pre-
cipitation of MLs at the injection site also contributes to the slow ab-
sorption phase of these drugs (Lo et al., 1985; Scott and McKellar,
1992). Parenteral administration of IVM and DRM resulted in greater
availability than oral administration in horses (Table 6). It has been
reported that in horses, lower and later Cmax but much greater AUC, T1/
2 and MRT values were observed after subcutaneous or intramuscular
injections of IVM (McKellar and Marriner, 1987; Perez et al., 2003;
Saumell et al., 2017) and DRM (Perez et al., 2010) compared to those
observed after oral administration (Table 6). However, although greater
plasma availability of IVM was observed, a lower efficacy (36–64%)
was obtained after intramuscular administration compared to that ob-
served following administration by the oral route (100% efficacy) in
horses (Saumell et al., 2017). The greater IVM efficacy observed against
adult cyathostomins following oral administration may be attributable
to the enhanced drug exposure of the worms located in the gastro-
intestinal lumen (Saumell et al., 2017). Similarly, it has been observed
that the higher activity of IVM was achieved against ascarids by the
paste formulation compared to the injectable administration (Lyons
et al., 1986).
Topical (pour-on) formulations of IVM, MXD, DRM and EPM have
been developed and licensed for use in cattle. Nevertheless, off-label
administrations of pour-on IVM and EPM formulations have been in-
vestigated to determine the potential for pour-on administration as an
C. Gokbulut, Q.A. McKellar
alternative treatment route in equine species. Large variations in
pharmacokinetics are evident among animal species after pour-on ad-
ministration of IVM or EPM as a result of anatomic and physiologic
variation, irregular absorption of drug from the site of application as-
sociated with differences in coat length and hair density and the var-
iation of the environmental conditions to which the animals were ex-
posed during the studies. The pour-on formulations of MLs were
administered at higher dose rates, their plasma availabilities via the
topical route were much lower compared to oral or subcutaneous ad-
ministration due to their poor or limited absorption through the skin, as
previously reported in different equine species including horses
(Gokbulut et al., 2010b, b) and donkeys (Gokbulut et al., 2011, 2013)
(Table 4) as it has been demonstrated in cattle (Gayrard et al., 1999).
In horses, it was shown that the plasma concentration and systemic
availability of IVM were lower, but the plasma persistence was pro-
longed with much longer terminal half-life after pour-on administration
(F%: 6.99) compared with the oral route (F%: 48.13) (Gokbulut et al.,
2016b). It is likely that after pour-on administration, MLs bind physi-
cally to the haircoat at the application site further preventing absorp-
tion or that the molecules become trapped in the skin or precipitated at
the skin surface at the site of application and are very slowly released
from there. Although the plasma concentration is much lower after
pour-on administration in animals, the values of terminal half-life and
MRT are significantly longer and these differences suggest slow ab-
sorption from the skin which limits later elimination of IVM. It has been
shown that absorption was the rate-limiting kinetic process for pour-on
formulations and the terminal half-life represents the half-life of ab-
sorption of MLs in cattle thus conferring a flip-flop effect in which the
disposition of the drug in the body and its elimination is controlled by
the absorption process (Gayrard et al., 1999).
Moreover, the kinetic parameters of pour-on EPM in horses
(Gokbulut et al., 2016b) were different from those reported for pour-on
IVM following topical administration with the same dose rate (0.5 mg/
kg BW) in horses (Gokbulut et al., 2010b). Thus, the plasma con-
centration and persistence of pour-on EPM were much lower and
shorter than those of pour-on IVM. Furthermore, EPM was absorbed
and reached peak plasma concentration and was eliminated from
plasma much faster, resulting in lower and shorter plasma availability
compared with pour-on IVM (Table 4). This faster absorption process of
pour-on EPM could be correlated to different environmental or climatic
conditions. It was shown that the exposure of animals to rain or direct
UV-radiation changed the plasma dispositions of IVM in cattle after
pour-on administration. It has been suggested that the exposure to rain
could result in the removal of active compound from body surface of
animals and that the exposure to direct UV-radiation from sun could
cause increased cutaneous blood circulation at the administration site
and ⁄ or decreased viscosity of the drug pour-on administered
(Gokbulut et al., 2012a). However, the study with pour-on IVM
(Gokbulut et al., 2010b) was performed in December when the UV-
radiation is low, and the later study was performed in June when the
UV-radiation is relatively more intense. Moreover, the difference in the
pharmacokinetics between pour-on EPM and pour-on IVM could be due
to the different pharmaceutical formulations and physicochemical
properties of the drugs used. The rate of penetration of a drug will
depend on its lipophilicity and EPM is the least lipophilic of the en-
dectocides compounds (Sheriff et al., 2002). In addition, MLs are P-gp
substrates and their coefficients of lipophilicity and P-gp and Breast
Cancer Resistance Protein (BCRP) effluxes determine their kinetic dis-
positions or concentrations in different tissues of the host (Lespine
et al., 2012). The excipients in the pharmaceutical formulations of
endectocides may also alter their absorption from the application site
and hence their plasma availability (Lo et al., 1985); The pharmaceu-
tical formulation of pour-on EPM differs from pour-on IVM because the
IVM is formulated in crodamol, triethanolamine and isopropyl alcohol,
whereas EPM formulation contains butylated hydroxytoluene, propy-
lene glycol and octanoate decanoate as a vehicle. In addition, the
45
Veterinary Parasitology 261 (2018) 27–52
different physiological status of horses may alter the plasma disposi-
tions of either molecules. In the study by Gokbulut et al. (2016b) the
horses were lactating and, the lactation status of the horses could be
associated with faster plasma elimination (T1/2: 1.37 days) of EPM,
whereas the horses were not lactating (T1/2: 7.18 days) in the previous
study using IVM (Gokbulut et al., 2010b).
Although IVM and DRM showed similar absorption patterns, the
plasma elimination and AUC of IVM were initially faster and larger,
respectively in comparison to DRM following oral administration in
donkeys (Gokbulut et al., 2005). Similar differences between IVM and
DRM were also observed in horses (Gokbulut et al., 2001b) and rumi-
nants (Lanusse et al., 1997; Toutain et al., 1997; Barber et al., 2003).
These differences may be associated with different physicochemical
properties between DRM and IVM. Both compounds are avermectins
but have a structural difference between in the dihydro modification at
the 2223 position. The higher persistence of DRM compared to that of
IVM could confer persistent efficiency against equine parasites due to
its longer retention time in plasma.
The results from IVM in administered donkeys (Gokbulut et al.,
2005) differ substantially from those reported for horses (Marriner
et al., 1987; Perez et al., 1999; Gokbulut et al., 2001b; Perez et al.,
2003; Gokbulut et al., 2010b) at same dose rate and administration
route. In donkeys, larger AUC and longer MRT of both molecules in
plasma and faeces reflect longer drug persistence and greater absorp-
tion from the gastrointestinal tract in donkeys compared to horses
(Gokbulut et al., 2001b). In contrast to this, Marriner et al. (1987);
Perez et al. (1999, 2003) and Gokbulut et al (2010b) observed a much
larger AUC with a higher Cmax for IVM in horses following oral ad-
ministration compared with IVM in donkeys. Reasons for the differ-
ences among the studies are unknown but may be associated with diet,
breed, parasitological status and anatomic characteristics in donkeys
compared with horses.
In two different studies, the plasma dispositions of EPM have been
investigated in milking (Gokbulut et al., 2013) and non-milking don-
keys (Gokbulut et al., 2011) following pour on administration at a dose
of 0.5 mg/kg BW. Although MRT values in both studies were similar,
Cmax and AUC values were almost 2 times smaller in the milking don-
keys compared with those in the non-milking donkeys. The reason for
the lower systemic exposure of EPM in milking-donkeys is unclear.
These differences may in part be due to differences in methodology,
since different body size, length of haircoat and environmental condi-
tions such as sun exposure can cause differences in drug absorption and
systemic availability of drugs following pour-on administration
(Gokbulut et al., 2011, 2012b). The faster elimination processes of EPM
in this research compared to the previous study (Gokbulut et al., 2011)
could be due to the different physiologic status of the study animals.
The lactation status of the donkeys could be associated with faster ex-
cretion of EPM. In addition, the results observed in the milking donkeys
(Gokbulut et al., 2013) indicated that the milk to plasma ratio (0.16) is
similar to those reported in cattle (0.1) (Alvinerie et al., 1999). The milk
excretion of oral IVM and pour-on EPM have also been investigated in
horses. Due to the poor systemic availability of pour-on EPM, its milk
availability (AUCmilk: 8.51 ng.d/mL) was much lower compared with
oral IVM (AUCmilk: 15.64 ng.d/mL). However, pour-on EPM displayed a
much greater milk partitioning (AUCmilk/plasma: 0.48) compared with
oral IVM (AUCmilk/plasma: 0.19) and compared with milk partitioning
results obtained in different animal species (Shoop et al., 1996a; Dupuy
et al., 2001a; Gokbulut et al., 2013). The origin of these differences is
unclear, although the anatomical and physiological variations of each
species do not appear to play an important role because it has been
shown that pour-on EPM displayed a similar extent of milk partitioning
in cows and donkeys (AUCmilk/plasma: 0.11 and 0.16, respectively)
(Alvinerie et al., 1999; Gokbulut et al., 2013). Due to the high lipo-
philicity of the MLs, they are likely to partition into milk. However, the
fat content of mare’s milk (12.1 g/kg) is similar to donkey’s milk
(10.6 g/kg) and is nearly 3 times lower compared to cow’s milk (36.1 g/
C. Gokbulut, Q.A. McKellar
kg) (Malacarne et al., 2002), suggesting that factors other than milk fat
composition are involved in the excretion pattern of EPM and IVM in
horse milk. Transport proteins such as BCRP are located in mammary
glands during lactation, where they transport xenobiotic substrates
from plasma to milk (Jonker et al., 2005) and BCRP plays an important
role in the milk partitioning of endectocides into milk (Lespine et al.,
2012). In this respect, it would also be of great interest to understand
the different transportation patterns of these drugs in equine species.
The mean highest drug concentrations in donkey milk (Cmax: 2.69 ng/
mL for pour-on EPM) and mare’s milk (Cmax: 4.59 ng/mL for oral IVM
and 3.84 ng/mL for pour-on EPM) were much lower compared to the
maximum residue limits (MRL), which were established as 20 μg/kg for
EPM and 10 μg/kg for IVM in bovine milk by the joint FAO/WHO Ex-
pert Committee (EPMAR, 2014). These results indicated that both oral
IVM and pour-on EPM have minimal disposition rates into milk, which
is important if the donkey or mare’s milk is to be used for human
consumption.
Following pour-on administration, the depletion of IVM or EPM at
the application and far from the application sites were also determined
in horses (Gokbulut et al., 2010b) and donkeys (Gokbulut et al., 2011),
respectively. Relatively high concentrations and slow degradation of
IVM or EPM in hair samples collected from the application site was
observed in both studies. In addition, detectable concentrations were
observed in the hair samples collected far away from the application
site and this was considered likely due to the excretion of compounds
by sebum secretion (after absorption of a fraction of IVM or EMP).
Sebum secretion was previously reported in humans with scabies after
an oral treatment with IVM (Haas et al., 2002). These results indicate
that IVM or EPM was available at the skin surface for a long period of
time after pour-on administration and this probably provides longer
persistence of efficacy for ectoparasites in horses and donkeys. More-
over, differences in the physiological and histological structure of skin
or haircoat between donkeys and horses probably play an important
role for transfer of the drug from the surface of the skin into the sys-
temic circulation.
5. Other anthelmintics
5.1. Closantel
Closantel is a salicylanilide (Fig. 5) which acts by uncoupling oxi-
dative phosphorylation (Corbett and Goose, 1971; Prichard, 1978).
Closantel is not thought to be extensively metabolized, although Glu-
curonide metabolizes of other members of the salicylanilide group have
been identified (Broome and Jones, 1966). Toxicity is thought to be
associated with uncoupling of phosphorylation in the mammalian host
and the salicylanilides generally have a rather narrow therapeutic index
of between 4 and 6. Specific signs of blindness and increased defecation
respectively have been recognized in sheep treated with the related
drugs Rafoxanide and Oxyclozanide (Mrozik et al., 1969; Boray et al.,
1967).
Although there is no information on the pharmacokinetics of
Fig. 5. Chemical structure of Closantel.
46
Veterinary Parasitology 261 (2018) 27–52
Closantel in horses it is known to have a very long terminal elimination
half-life in sheep with detectable concentrations measurable in plasma
for up to approximately 100 days after oral administration of a ther-
apeutic dose (7.5 mg/kg) (Mohammed-Ali and Bogan, 1987). This
persistence in plasma has been attributed to strong binding to plasma
albumin which has a turnover rate of about 16.6 days (Holmes et al.,
1968) and this may also explain it’s activity against parasites which
ingest host plasma proteins such as F. hepatica.
It has been demonstrated that in horses, closantel was highly ef-
fective against adult S. vulgaris, S. edentatus, A. perfoliata and
Triodontophorus spp., and larval stages of S. vulgaris and Gasterophilus
intestinalis following oral administration at doses of 20 or 40 mg/kg BW
(Guerrero et al., 1983). In addition, naturally infected horses with F.
hepatica were successfully (100% efficacy) treated with closantel fol-
lowing oral administration at a dose of 15 mg/mL BW (Alcaino and
Aguilar, 1985). Closantel displayed a high anthelmintic activity against
F. hepatica in experimentally infected ponies after oral administration at
a dose of 10 mg/kg BW (Dorchies et al., 1990).
5.2. Praziquantel
Praziquantel (Fig. 6) has been classified as an isoquinoline and has
been marketed in animal and human medicine for its activity against
cestodes and trematodes. It is metabolised to less active glucuronide
and sulfuric conjugates in laboratory animals (Diekmann and Buhring,
1976). It has been shown to bind to parasite Glutathione S- transferase
(McTigue et al., 1995) and to alter parasite intracellular calcium con-
centrations (Harnett, 1988) and its effects are manifest as parasite te-
gumental disruption and muscular contraction. Praziquantel is gen-
erally very well tolerated in all animals for which it has been used
therapeutically with a very large therapeutic index in laboratory ani-
mals (Frohberg, 1984). There is no data on the pharmacokinetics of
Praziquantel in horses but in man it is known to be rapidly and largely
(90%) absorbed following administration and subsequently rapidly
eliminated with a plasma clearance of 28 L/kg (Leopold et al., 1978).
Clinical trials by Slocombe et al. (2007) showed that the efficacy of
praziquantel horse paste 9% was 90.9, 100 and 100% against A. per-
foliata, A. magna and A. mamillana, respectively. and safe in horses.
Horses infected with A. perfoliata were successfully treated with prazi-
quantel at a dose of 1.5 mg/kg BW (Abbott et al., 2008). Praziquantel in
combination with MLs such as IVM, DRM, ABM or MXD as double
combination have been developed in order to effectively treat equine
nematode and cestodes parasites. Triple combinations with addition of
OFZ, FBZ or PYR + have been developed by pharmaceutical companies
for the treatment of parasites in equine species and may extend the
spectrum of activity and delay the development of drug resistance to
equine parasites (Table 2).
5.3. Trichlorfon
Trichlorfon is an organophosphate compound (Fig. 7) and in
common with other members of this group of compounds acts to inhibit
the enzyme acetyl cholinesterase. Acetyl cholinesterase is responsible
Fig. 6. Chemical structure of Praziquantel.
C. Gokbulut, Q.A. McKellar
Fig. 7. Chemical structure of Trichlorfon.
Fig. 8. Chemical structure of Piperazine.
for the degradation of the neurotransmitter acetyl choline and it is
likely that this is the major effector mechanism for its antiparasitic
activity (Bueding et al., 1972). It may be that the paralysis of nema-
todes associated with organophosphate activity is more effective when
it results in their removal (for example by gut peristalsis) from their
predilection site. Trichlorfon inhibits acetylcholinesterase in mamma-
lian plasma and brain but does not cause the polyneuritis associated
with some other organophosphate compounds when used at normal
therapeutic dosages (Wolmstedt et al., 1978). During the interaction of
organophosphorus compounds with acetyl cholinesterase an initial
weak bond is formed with a serine group on the enzyme. This bond can
be dephosphorylated using a nucleophilic competitor such as prali-
doxime and this forms the basis of treatment in intoxication. Ultimately
if the bonds between the phosphate and its methyl, ethyl or amino
groups are cleaved then the phosphorous becomes relatively negative
and thus insensitive to nucleophilic attack (it has “aged”). In this event
cholinesterase activity will only reappear if new enzyme is synthesized.
In the absence of pralidoxime the antimuscarinic drug atropine is used
in the treatment of organophosphate toxicity to control muscarinic
stimulation of the autonomic nervous system responsible for increased
secretions, bronchoconstriction, intestinal motility and miosis, but does
not control muscle fasciculations associated with nicotinic stimulation
at neuromuscular junctions. (McKellar, 1997a). Organophosphates are
rapidly absorbed following oral administration and are metabolised by
liver phosphatases which hydrolyse the parent molecules, and which
have been shown to be host species specific (Aldridge, 1954), Meta-
bolites are subsequently excreted in urine.
Efficacy and safety studies on trichlorfon reported that doses of
40 mg/kg BW and less were generally well tolerated by horses (Drudge
et al., 1976). This investigation indicated that trichlorfon was highly
effective (efficacy between 97–100%) against G. intestinalis and G. na-
salis, P. equorum O. equi, S. vulgaris and S. edentatus. Higher dose rates
(60 and 80 mg/kg BW) administered by stomach tube caused moder-
ately severe colic and diarrhea, whereas a dose of 80 mg/kg given in the
feed resulted in only a transient softening of the faeces. More than two
thousand treatments of trichlorfon did not cause notable adverse clin-
ical effects at a dose of 35–40 mg/kg in pregnant and nonpregnant
mares, stallions, suckling and weanling foals, and yearlings (Drudge
et al., 1976).
5.4. Piperazine
Piperazine (Fig. 8) is a hexahydropyrazine and the citrate or dihy-
drochloride salts have been utilised in horses. It has been suggested that
47
Veterinary Parasitology 261 (2018) 27–52
piperazine causes a flaccid paralysis in ascarid nematodes by acting as
an antagonist at cholinoreceptors (Norton and De Beer, 1957). How-
ever, Martin (1982, 1985) has shown that it is a GABA agonist of low
potency acting on extra synaptic GABA receptors to cause increased Cl−
conductance and consequent hyperpolarisation. Piperazine has a high
therapeutic index with LD50 values of more than 4000 mg/kg in mice
for both the hexahydrate and adipate salts (Cross et al., 1954). At very
high dosages, incoordination, hyperaesthesia and diarrhoea have been
recorded in dogs and cats (Greenberg et al., 1958; Stoffman and
Braithwaite, 1976).
Piperazine is available as a powder for use in the horse and in zoo
canids and felines. It is used in the horse mainly because of its good
activity against Parascaris (Bogan and Duncan, 1984). In an earlier
study, it was reported that piperazine citrate at 88 mg/kg BW was fully
effective against mature and immature Parascaris in unweaned and
weaned foals, but the activity of piperazine dihydrochloride at doses of
44 mg/kg or 88 mg/kg BW was significant but incomplete against
Parascaris in yearlings (Drudge et al., 1960). The various dose levels of
the piperazine compounds were all successful in reducing the count of
strongylid eggs for 4 weeks after treatment. Recently, Lyons et al.
(2016) reported that piperazine has good but incomplete activity
against strongyles and no activity against Strongyloides following oral
administration at a dose of 112 mg/kg BW in horses. There is very little
information available on the pharmacokinetics of Piperazine in horses.
It is known to have low and variable absorption from the gastro-
intestinal tract in man (Fletcher et al., 1982) and it maybe the un-
absorbed gastrointestinal concentrations which confer activity.
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