Arch. Pharm. Res.
DOI 10.1007/s12272-014-0517-z
REVIEW
Interactions between herbs and antidiabetics: an overview
of the mechanisms, evidence, importance, and management
Shaheed Ur Rehman • Min Sun Choi •
Kevin Choe • Hye Hyun Yoo
Received: 26 February 2014 / Accepted: 10 November 2014
Ó The Pharmaceutical Society of Korea 2014
Abstract Complementary and alternative therapies are
quickly gaining importance because they are perceived to
be free of side effects due to their natural origin. However,
herbal remedies are complex mixtures of bioactive entities,
which may interact with prescription drugs through phar-
macokinetic or pharmacodynamic mechanisms and some-
times result in life-threatening consequences. In particular,
diabetes patients are often treated with multiple medica-
tions due to different comorbidities, and such patients use
antidiabetic medications for their entire lives; thus, it is
important to make the public aware of herb interactions
with antidiabetic drugs. In this paper, we summarize the
reports available on the interaction of herbal remedies with
oral hypoglycemic agents and describe mechanisms, pre-
clinical or clinical evidence, importance, and management
strategies.
Keywords Herb–drug interaction
Antidiabetics

Mechanism
Evidence
Management
Introduction
The use of medicinal plants to treat diseases is probably the
first method used by humanity to cope with illness, and
medicinal plants are used therapeutically around the world
as important components of various traditional medicine
systems (Solimene et al. 2007). In particular, the high
prevalence of chronic disorders such as obesity,
S. Rehman
M. S. Choi
K. Choe
H. H. Yoo (&)
Institute of Pharmaceutical Science and Technology and College
of Pharmacy, Hanyang University, Ansan,
Gyeonggi-do 426-791, Republic of Korea
e-mail: yoohh@hanyang.ac.kr
hypertension, pain syndromes, and anxiety, as well as a
desire for good health, collectively lead to the use of herbal
medicines (Tachjian et al. 2010). Herbal medicines are
quickly gaining importance because they are perceived to
be free of side effects due to their natural origin (Walker
and Donovan 1999). However, herbal remedies are com-
plex mixtures of organic chemicals and have many
potential adverse effects owing to their active ingredients
and the interactions of these ingredients with conventional
drugs, which can sometimes have life-threatening conse-
quences (Bent et al. 2005). It has been well documented
that significant effects on pharmacokinetics and/or phar-
macodynamics can occur through herb–drug interaction
(Butterweck and Derendorf 2008; Tarirai et al. 2010),
which has led to increased concern regarding the safety of
co-administration of herbal products with drugs (Chavez
et al. 2006; Hafner-Blumenstiel 2011; Izzo and Ernst 2009;
Marchetti et al. 2007; Skalli et al. 2007).
Unlike conventional drugs, herbal products contain a
complex mixture of bioactive entities, each of which may
or may not provide therapeutic activity. Often a complete
characterization of all the chemical constituents from a
natural product is unavailable. Additionally, the chemical
makeup of a natural product may vary depending on the
part of the plant processed (stems, leaves, roots), season-
ality, and growing conditions. While the complex nature of
natural products complicates determination of drug–herb
interactions, the manufacturing process also contributes to
the complexity of these processes.
The potentially dangerous effects of herbs in patients
already taking prescription medications is a significant
concern, particularly for those patients currently taking
multiple medications, which are often prescribed by mul-
tiple physicians who may or may not be in communication
with each other regarding their medical reasoning.
123
 S. Rehman et al.

Table 1 Important CYP isonzymes subfamilies and their acting herbs

CYP Interacting nature Acting herb References

CYP1A2 Inhibitor Melatonin Yeleswaram et al. (1999)

CYP1A2 Substrates Sweet wormwood Greenblatt et al. (2006 and Williamson et al. (2013)
CYP2C8 Inducer Flavonoids Cermak and Wolffram (2006), Choi et al. (2004), Kim et al. (2005)
Substrate Goldenseal Mohutsky et al. (2006) and Williamson et al. (2013)
Quercetin Choi et al. (2004)
CYP2C9 Inducer Ginkgo Etheridge et al. (2007), Gaudineau et al. (2004), Moltke et al.
(2004), Sugiyama et al. (2004a, b), Yale and Glurich (2005)
St. John’s wort Xu et al. (2008)
Inhibitor Isoflavones (puerarin) Guo et al. (2014)
Substrate Resveratrol Yu et al. (2003b)
CYP2C19 Inducer Ginkgo Etheridge et al. (2007), Gaudineau et al. (2004), Moltke
et al. (2004) and Sugiyama et al. (2004b)
Inhibitor Resveratrol Yu et al. (2003b)
CYP2D6 Inducer Valerian Hellum et al. (2007) and Vale (1998)
Inhibitor Aloe vera Djuv and Nilsen (2012)
Substrate Goldenseal Gurley et al. (2005, 2008)
CYP3A4 Inducer Danshen Qiu et al. (2010, 2008)
Ginseng (panax) Malati et al. (2012)
St. John’s wort Goey et al. (2014)
Turmeric Hou et al. (2007) and Sugiyama et al. (2006)
Goldenseal Beckert et al. (2007), Budzinski et al. (2000, 2007),
Chatterjee and Franklin (2003)
Inhibitor Andrographis Ooi et al. (2011)
Elder Langhammer and Nilsen (2014)
Aloe vera Djuv and Nilsen (2012)
Isoflavones (puerarin) Guo et al. (2014)
Substrate Rooibos Matsuda et al. (2007)
Echinacea Gilbert (1997), Gorski et al. (2004), and Rowin and Lewis (1996)

Furthermore, an increasing percentage of the public is
taking herbs, often without their physician’s knowledge.
Therefore, it is important for clinical practitioners, herb-
alists, and patients to understand the nature of herb–drug
interactions to avoid any undesirable side effects cause by
coadministration of herbal medicines and drugs.
Diabetes mellitus (diabetes) is a group of chronic met-
abolic diseases characterized by high blood sugar levels
over a prolonged period. Untreated diabetes can cause
many complications, which range from acute effects such
as diabetic ketoacidosis and nonketotic hyperosmolar coma
to more serious complications such as heart disease, stroke,
kidney failure, foot ulcers, and damage to the eyes (Walker
et al. 2013). Therefore, continuous management of blood
sugar levels is important in patients with diabetes, and such
control can be achieved through diet, exercise, and use of
appropriate medications with insulin injections or oral an-
tidiabetics. As the number of people with diabetes increa-
ses, so does the number of those who try alternative means
to manage the disease, including the use of herbs. In
particular, many people often take herbal remedies with
oral hypoglycemic agents without sufficient caution.
However, coadministered herbs may alter the pharmaco-
kinetic profile of hypoglycemic agents or potentiate/
antagonize their pharmacological effects, and thus lead to
side effects resulting from failure to regulate blood sugar
levels. These risks are particularly serious due to the long-
term nature of therapy for diabetic patients. Therefore, this
paper reviewed herb–drug interactions involving antidia-
betic drugs, with a focus on mechanisms, clinical evidence,
importance, and management strategies.
Mechanisms of herb–drug interactions
The basic concept of interaction is that consumption of two
substances (herbs, drugs, nutrients, foods) at the same time,
or within a short time, will result in physiological effects
that are different from a simple summation of the effects of
either substance alone.

123
Interactions between herbs and antidiabetics
Overlapping substrate specificity in the biotransforma-
tional pathways of physiological systems is seen as the
major reason for drug–drug, food–drug, and herb–drug
interactions (Marchetti et al. 2007). The ability of different
chemical moieties to interact with receptor sites and alter
the physiological environment can explain pharmacody-
namic drug interactions, while pharmacokinetic interac-
tions arise from altered absorption and interference in
distribution patterns, as well as changes in, and competition
for, metabolic and excretory pathways (Izzo and Ernst
2009). It is therefore convenient to consider separately the
mechanisms involved in pharmacokinetic and pharmaco-
dynamic interactions.
Pharmacokinetic herb–drug interactions
The major underlying mechanisms of pharmacokinetic
drug–herb interaction, as with drug–drug interaction, are
the induction and inhibition of intestinal and hepatic met-
abolic enzymes such as those of the CYP enzyme family,
as well as drug transporters and efflux proteins (Meijerman
et al. 2006; Yoo et al. 2007; Nowack 2008; Yoo et al.
2008). In particular, the pre-systemic activity of CYP
enzymes often influences oral bioavailability of drugs, thus
the modulating activity of co-administered herbal products
on CYP function has been shown to result in pronounced
changes in the blood levels of the affected drugs (Brown
et al. 2008).
The CYP system is a family of monooxygenase
enzymes mainly found in intestinal and liver cells that
catalyzes several phase I metabolic processes, including
oxidation, hydroxylation, S-and O-demethylation, and
oxidative deamination of more than 70 % of prescription
drugs (Karyekar et al. 2002). The CYP superfamily is
involved in biotransformation of a wide range of xenobi-
otics and endogenous compounds (Hiratsuka 2012; Nebert
and Russell 2002). CYP enzymes belonging to families 1,
2, and 3 are principally involved in xenobiotic metabolism,
while others play a major role in the formation and elim-
ination of endogenous compounds such as hormones, bile
acids, and fatty acids (Amacher 2010; Norlin and Wikvall
2007). The most important CYP enzymes responsible for
drug metabolism in humans are CYP1A2, CYP2A6,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and
CYP3A5 (Ono et al. 1996; Boullata 2005). Because some
herbs and drugs may be substrates of the same CYP iso-
enzymes, they may inhibit or induce the activity of these
CYP isoenzymes when ingested concomitantly (Wang and
Chou 2010; National Institutes of Health Office of Dietary
Supplements 2013). The important CYP subfamilies and
herbs on which they act are shown in Table 1.
Absorption of drugs can be impaired when herbs that
contain hydrocolloidal fibers, gums, and mucilage are
taken together. Such products include aloe gel, flaxseed,
marshmallow, psyllium, and rhubarb (Samson 1982).
These herbals can bind to drugs and prevent absorption,
and thus reduce systemic availability. Drug displacement
of highly protein-bound drugs by other compounds may
result in increased activity of the displaced drug. Although
displacement of protein-bound drugs has been described as
a source for potential drug interactions, there are no doc-
umented reports of herb–drug interactions attributable to
displacement of drugs from protein-binding sites (Wang
and Chou 2010). Altered renal clearance is another
potential mechanism underlying herb–drug interactions, in
which herbal products capable of interacting with renal
functions alter renal drug elimination. Changes in renal
function can result from inhibition of tubular secretion,
tubular reabsorption, or glomerular filtration (Isnard Bagnis
et al. 2004). Herbal products consumed as diuretics are
often capable of altering renal function, but their mecha-
nisms of herbal diuresis are complex and non-uniform.
Some herbs increase the glomerular filtration rate, but do
not stimulate electrolyte secretion, while others act as
direct tubular irritants (Al-Ali et al. 2003; Crosby et al.
2001). Thus, herbs that can interfere with the renal clear-
ance of a drug should be considered to have the potential to
produce pharmacokinetic herb–drug interactions (Wang
and Chou 2010), and representative examples are discussed
below.
In vitro assessments with allicin, fresh garlic, or com-
mercially prepared garlic supplements showed that they
had modest inhibitory activities (\50 %) against human
CYP2C9, CYP2C19, and CYP3A4 isoforms (Foster et al.
2001; Zou et al. 2002; Kim et al. 2012). It has been well
established that St. John’s wort (SJW) can modulate CYP
subfamilies 2C and 3A, as well as several ABC efflux
transporters (Kober et al. 2008; Madabushi et al. 2006;
Whitten et al. 2006; Zhou and Lai 2008). More than 70 %
of all prescription medications are susceptible to SJW-
mediated interactions, the consequences of which include
decreased oral bioavailability, enhanced systemic clear-
ance, and reduced drug efficacy (Williamson et al. 2013).
Ginkgo biloba has a modest inhibitory effect on CYP
activity (Smith et al. 2001; Sun et al. 2002; Uchida et al.
2006; Fan et al. 2009a, b), and induces expression of
CYP3A4 (Jiang et al. 2006), CYP2C9 (Greenblatt et al.
2006), and CYP2C19 (Yin et al. 2004). In vitro, a Devil’s
claw (genus Harpagophytum) extract moderately inhibited
the activity of CYP2C8, CYP2C9, CYP2C19, and
CYP3A4 (Unger and Frank 2004).
Pharmacodynamic herb–drug interactions
Some constituents from herbs may act on identical drug
target molecules (e.g. receptors or enzymes), resulting in
123

synergistic or antagonistic herb–drug interactions (Asdaq
and Inamdar 2010; Dasgupta et al. 2010; Van den Bout-van
den Beukel et al. 2008; Kim et al. 2010; Nivitabishekam
et al. 2009). Synergistic or additive (enhanced) effects may
lead to toxicity and complicate the dosing regimens of
long-term medications, while antagonistic interactions may
result in decreased efficacy and therapeutic failure (Ma
et al. 2009).
Synergistic or additive interactions
An herb might produce the same effect as a drug and thus
enhance this effect upon coadministration (Kang and Park
2010; Scott and Elmer 2002; Williamson et al. 2013).
Therefore, herbal sedatives, anticoagulants, antihyperten-
sives, and other drugs could increase the effects of con-
ventional drugs taken simultaneously for the same purpose.
For example, additive blood-glucose-lowering effects are
produced when agrimony extract is taken with anti-dia-
betics (Gray and Flatt 1998; Swanston et al. 1990). The
hypnotic activity of benzodiazepines is increased by vale-
rian, and the anticoagulant action of warfarin is enhanced
by gingko, garlic, and ginger (Kuhn 2002; Scott and Elmer
2002; Fetrow et al. 1999).
Antagonistic interactions
An herb might produce an effect that is contrary to the
effect desired by a coadministered drug, thereby reducing
the effect of the drug (Scott and Elmer 2002; Williamson
et al. 2013). Ephedra or caffeine-containing herbs (cola nut,
guarana, mate, green tea), often used in combination to
produce additive cardiovascular effects in many herbal
weight-loss products, may antagonize the effects of anti-
hypertensive medications (Scott and Elmer 2002; Wil-
liamson et al. 2013).
Diabetes is a growing epidemic that affected more than
350 million people worldwide in 2011, and its prevalence
is expected to increase to approximately 550 million by
2030 (Whiting et al. 2011). The pharmacological treatment
of hyperglycemia in patients with type 2 diabetes mellitus
(T2DM) is usually initiated with oral antidiabetic drug
monotherapy, but combination therapy with different oral
antidiabetics or parenteral therapy with insulin may be
needed as the disease progresses. Moreover, to reduce
cardiovascular morbidity and mortality, multitargeted
treatment, including antihypertensive, lipid-lowering, and
antiplatelet drugs, is often employed in T2DM patients
(Gaede et al. 2008). Owing to different comorbidities,
T2DM patients are often treated with multiple medications
in a practice referred to as polypharmacotherapy, which is
especially common in the elderly (Caughey et al. 2010).
123
S. Rehman et al.
Thus, this patient group is at an increased risk of harmful
drug–drug interactions and herb–drug interactions.
Based on both in vitro and pharmacogenetic data, DDIs
and HDIs involving oral antidiabetics and the main CYP
enzymes, including CYP2C8, CYP2C9, CYP2C19, and
CYP3A4, have been identified. This indicates the need for
increased understanding of the effects of many clinically
important HDIs on the pharmacokinetics of oral antidia-
betics. Available clinical and experimental evidence shows
that pharmacodynamic interactions are also a major class
of herb–antidiabetics interactions.
Antidiabetic–herb interactions
The most common interactions of herbs with antidiabetic
drugs are those that result in a rise or fall in blood glucose
levels, thereby disturbing the control of diabetes. Antidia-
betic drugs that have been found to have a probability of
interacting with coadministered herbal products include
CYP2C8 substrates pioglitazone, repaglinide, and rosiglit-
azone; CYP2C9 substrates glibenclamide, glimepiride,
glipizide, nateglinide, and rosiglitazone; CYP2C19 sub-
strate proguanil; and CYP3A4 substrates pioglitazone and
repaglinide (Bertram 2012; Anthony and Gregory 2014).
Herb–drug interactions related to antidiabetic drugs are
summarized in Table 2. The herb–drug interactions of
several selected herbs are described in detail below.
Aloe vera
In diabetic patients, treatment with A. vera has been shown
to cause significant reduction in blood glucose and blood
pressure, as well as to improve the lipid profile (Choudhary
et al. 2014). Due to its hypoglycemic nature, A. vera
interacts with anti-diabetics.
Evidence of herb–drug interaction
In obese individuals with prediabetes or early untreated
diabetes mellitus, treatment with an A. vera gel complex
reduced the body weight, body fat mass, and insulin
resistance (Choi et al. 2013). Diabetic patients treated with
A. vera juice with or without glibenclamide showed
reduced blood-glucose levels (Bunyapraphatsara et al.
1996; Yongchaiyudha et al. 1996). Yagi showed a possible
effect of long-term ingestion of A. vera gel metabolites on
insulin sensitivity (Yagi 2014). In high-fat diet-induced
mice, 3 weeks of treatment with aloesin and aloesinol
decreased plasma insulin levels by 37.9 and 46.7 %,
respectively. In diabetes (db/db) mice, a chromone-stan-
dardized aloe-based composition decreased fasting tri-
glyceride and plasma glucose levels by 33.7 and 46.0 %,
Interactions between herbs and antidiabetics

Table 2 Herb–drug interactions related to antidiabetic drugs

Interacting Herb–drug Mechanism type Possible interacting antidiabetic References
herb interactions severity drugs
(Williamson et al.
2013)

Aloe vera ??? Pharmacokinetics (CYP3A4) Pioglitazone, repaglinide Djuv and Nilsen (2012) and
Pharmacodynamics (enhancement Tseng-Crank et al. (2013)
in adipose tissue insulin signaling
pathway)
Andrographis ?? Pharmacokinetics (Inhibit Glibenclamide, glimepiride, Pan et al. (2011a, b), Ooi et al.
paniculata CYP2C9, CYP2C19, CYP2D6, glipizide, nateglinide, (2011) and Yu et al. (2003a)
CYP3A4) rosiglitazone, pioglitazone,
Pharmacodynamics (glucose repaglinide
transporter (GLUT4))
Cassia ? Pharmacokinetics (inhibit CYP Glibenclamide, glimepiride, Appiah-Opong et al. (2008)
1A2, 2C9, 2D6 and 3A4) glipizide, nateglinide,
Pharmacodynamics (inhibit the rosiglitazone, pioglitazone,
glucose absorption from the small repaglinide
intestine)
Ginseng ?? Pharmacokinetics (CYP3A4) Pioglitazone, repaglinide Anderson et al. (2003), Liu
Pharmacodynamics (stimulate and et al. (2013a) Sen et al.
increase in insulin action and (2013), Sun et al. (2014) and
secretion; decrease in b-cell Kim et al. (2012)
mass)
Karela ?? Pharmacokinetics (CYP, through Glibenclamide, glimepiride, Appiah-Opong et al. (2008),
CYP2C9 and glutathione glipizide, nateglinide, Raza et al. (1996, 2000) and
S-transferase) rosiglitazone Raman and Lau (1996)
Pharmacodynamics (insulin-like
effects and stimulate insulin
secretion)
Lycium ?? Pharmacokinetics (improve glucose Glibenclamide, glimepiride, Zhao et al. (2005), Lam et al.
transport, CYP2C9 inhibitor) glipizide, nateglinide, (2001) and Williamson et al.
Pharmacodynamics (improving rosiglitazone (2013)
GLUT4 trafficking and
intracellular insulin signaling)
St. John’s ?? Pharmacokinetics (CYP 1A2, 2C9, Glibenclamide, glimepiride, Hruska et al. (2005) and Goey
wort 2C19, 2D6 and 3A4; Activator of glipizide, nateglinide, et al. (2014), Obach (2000),
the pregnane X receptor) rosiglitazone, pioglitazone, Xu et al. (2008), Moore et al.
Pharmacodynamics repaglinide (2000), Menegazzi et al.
(2008), and Richard et al.
(improving beta-cell function and
(2012)
survival; inhibitors of
adipogenesis of 3T3-L1 cells)
1
For interactions that are not considered to be of clinical significance, or where no interaction occurs
11
For interactions where there is doubt about the outcome of concurrent use, and therefore it may be necessary to give patients some guidance
about possible adverse effects, and/or consider some monitoring
111
For interactions where there is a potentially hazardous outcome, but where, perhaps, the data is poor and conclusions about the interaction
are difficult to draw

respectively, after 10 weeks of oral treatment (Yimam Mechanism

et al. 2013). Similarly, enhanced improvement in plasma
insulin levels and a statistically significant reduction in
triglyceride levels were observed in animals treated with
the same chromone-standardized aloe-based composition
(Yimam et al. 2014).
The metabolites of aloe polymannose, such as a man-
nooligosaccharide and short chain fatty acids, synergisti-
cally modulate insulin sensitivity in tissues with a
combination of phenolics, such as aloesin, aloe emodin,

123

and salicylate (Yagi 2014). Nutrigenomic studies were
conducted to elucidate the mechanism of the hypoglycemic
and insulin-sensitizing effects of A. vera, and the results
showed that A. vera reduced hepatic fat accumulation and
enhanced insulin signaling in adipose tissue. This study
provided a mechanistic explanation for the in vivo effects
of enhanced insulin sensitivity and decreased blood glu-
cose in mouse diabetes and prediabetes models (Tseng-
Crank et al. 2013). Moreoever, A. vera was found to exert
inhibitory effects on CYP3A4 and CYP2D6 (Djuv and
Nilsen 2012). Antidiabetic drugs pioglitazone and repa-
glinide are substrates of CYP3A4.
Importance and management
Aloe vera could be used to facilitate the maintenance of
healthy blood glucose levels (Yimam et al. 2013), and it is
clear that some oral preparations of A. vera might have
clinically important blood-glucose-lowering effects.
Indeed, A. vera has traditionally been used to treat diabetes.
It might therefore be prudent to increase the frequency of
blood-glucose monitoring if patients taking antidiabetic
medication wish to try oral A. vera preparations (Wil-
liamson et al. 2013).
Andrographis paniculata
Andrographis paniculata is an herb that is commonly used
by diabetic patients (Reyes et al. 2006). Due to its hypo-
glycemic nature, it interacts with conventional anti-
diabetics.
Evidence of interaction
Experimental evidence shows that water extract of A.
paniculata significantly prevents orally administered glu-
cose-induced hyperglycemia in nondiabetic rabbits without
affecting epinephrine-induced hyperglycemia (Borhanud-
din et al. 1994). Ethanolic extract of A. paniculata
administered orally twice daily for 14 days to streptozo-
tocin-induced diabetic rats significantly reduced fasting
serum glucose and increased body weight in a dose-
dependent manner (Zhang and Tan 2000). Andrographo-
lide at the effective dose (1.5 mg/kg) significantly attenu-
ated the increase in plasma glucose induced by an
intravenous glucose challenge test in normal rats. This
result suggests that andrographolide can increase glucose
utilization to lower plasma glucose in diabetic rats lacking
insulin (Yu et al. 2003a). According to Reyes et al., the
anti-diabetic potential of A. paniculata was demonstrated
by its restoration of impaired estrous cycle in alloxan-
induced diabetic rats (Reyes et al. 2006).
123
S. Rehman et al.
Mechanism
Potentially additive pharmacological effects are present.
Andrographolide enhanced the uptake of radioactive glu-
cose in the isolated soleus muscle of STZ-diabetic rats in a
concentration-dependent manner. Moreover, mRNA and
protein levels of the glucose transporter 4 (GLUT4) in
soleus muscle were increased after repeated intravenous
administration of andrographolide for 3 days (Yu et al.
2003a).
Andrographis paniculata ethanolic extract also resulted
in significantly lower levels of thiobarbituric acid-reactive
substances in the liver and kidney in comparison with
vehicle-treated rats, while significantly increasing the
activity of superoxide dismutase and catalase enzymes, as
well as hepatic glutathione concentrations, in diabetic rats
(Zhang and Tan 2000). Ethanolic and methanolic extracts
of A. paniculata showed potent inhibitory effects on
CYP3A4 and CYP2C9 activities (Ki values below 20 lg/
mL) (Pan et al. 2011a). The diterpenoids andrographolide
and 14-deoxy-11,12-didehydroandrographolide reduced
the mRNA and protein levels of CYP2D6 and CYP3A4
(Ooi et al. 2011). Andrographis paniculata inhibited
CYP2C19 activity (Pan et al. 2011b). Glibenclamide,
glimepiride, glipizide, nateglinide, and rosiglitazone are
substrates of CYP2C9, and pioglitazone and repaglinide
are substrates of CYP3A4.
Importance and management
These experimental studies provide limited evidence of the
possible blood-glucose-lowering properties of Androgra-
phis. Furthermore, because of the nature of the evidence,
applying these results in a clinical setting is extremely
difficult. However, if a patient taking antidiabetic drugs
wishes to take A. paniculata, it may be prudent to discuss
these potential additive effects (Williamson et al. 2013).
Cassia
Cassia fistula and Cassia occidentalis are ethnomedicinal
plants that are widely used in Indian and Chinese medicine
to treat diabetes.
Evidence of interaction
Wild leguminous seeds of C. fistula were investigated by
Singh and Bharadwaj for their hypoglycemic activity, and
were found to have marked hypoglycemic activity in nor-
mal albino rats, but not in alloxan-induced diabetic albino
rats (Singh and Bharadwaj 1975). Nirmala et al. (2008)
reported the hypoglycemic and hypocholesterolemic
effects of the hexane extract of stem bark of C. fistula in
Interactions between herbs and antidiabetics
normal and streptozotocin induced diabetic rats, and found
that the effect of the extract at 0.45 g/kg was found to be
comparable with that of glibenclamide, the reference drug.
The antioxidant and polyphenol contents of the extracts
might contribute to their antihyperglycemic and antilipi-
demic properties (Nirmala et al. 2008). Acute and chronic
oral dosing of aqueous bark extract of C. fistula in nor-
moglycemic and streptozotocin-induced diabetic rats sig-
nificantly lowered fasting blood glucose levels and rapidly
caused marked improvement in the oral glucose tolerance
test (Ratnasooriya et al. 2004). Cassia occidentalis exhib-
ited significant antihyperglycemic activity in normal and
alloxan-induced diabetic rats. The antidiabetic activity of
C. occidentalis may be due to the presence of flavonoids
(Malpani et al. 2010).
Mechanism
Aqueous bark extract significantly inhibited glucose
absorption from the small intestine and induced glycogen
accumulation in liver and skeletal muscle (Ratnasooriya
et al. 2004). Catechin from C. fistula possesses hypogly-
cemic, glucose oxidizing, and insulin mimetic activities
(Daisy et al. 2010). Cassia inhibited the enzyme activities
of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (Appiah-
Opong et al. 2008). Glibenclamide, glimepiride, glipizide,
nateglinide, and rosiglitazone are substrates of CYP2C9,
and pioglitazone and repaglinide are substrates of
CYP3A4.
Importance and management
Findings from animal studies indicate that C. fistula and C.
occidentalis extract possess antihyperglycemic properties,
and these results lend credence to the traditional ethno-
medical uses of the plant in the management of T2DM (Ali
et al. 2012). Due to the antidiabetic properties of C. fistula
and C. occidentalis, their combination with conventional
antidiabetics requires proper caution and careful manage-
ment. Furthermore, coadministration of CYP substrate
antidiabetic drugs with C. fistula and C. occidentalis may
lead to herb–drug interactions.
Ginseng
Ginsenosides are major bioactive constituents of ginseng
that are thought to be the main components responsible for
its antidiabetic effect (Xiong et al. 2010). Some ginseno-
sides, such as Rb1, Rb2, Rc, Re, Rg3, Rh2, and compound
K have been shown to possess anti-diabetic activities
(Xiong et al. 2010; Cho et al. 2006; Lai et al. 2006; Lee
et al. 2006, 2010; Kim et al. 2009; Li et al. 2012). Panax
notoginseng saponins (PNS) produced anti-hyperglycemic
and anti-obesity effects by improving sensitivity to insulin
and leptin in KK-Ay mice. Rb1 may be the primary
hypoglycemic component of PNS extract (Zhong et al.
2014). Due to their hypoglycemic nature, ginseng constit-
uents interact with conventional anti-diabetics.
Interaction evidence
Twelve weeks of supplementation with a selected Korean
ginseng treatment safely maintained good glycemic con-
trol, improved plasma glucose levels, and enhanced plasma
insulin regulation beyond that achieved by normal therapy
in people with well-controlled type 2 diabetes. Further
investigation with similarly selected Korean ginseng
treatments may support their clinical efficacy (Vuksan
et al. 2008).
In a study of nondiabetic subjects, no differences were
found in postprandial glycemia between those treated with
placebo and ginseng when these compounds were admin-
istered together with a glucose challenge. When ginseng
was taken 40 min before the glucose challenge, significant
reductions were observed. Thus, for nondiabetic subjects,
to prevent unintended hypoglycemia it may be important
that Panax quinquefolius (American ginseng; AG) be taken
with a meal (Vuksan et al. 2000a). Two-way analysis of
variance (ANOVA) demonstrated that treatment (0, 3, 6,
and 9 g AG), but not time of administration (120, 80, 40, or
0 min before the glucose challenge), significantly affected
postprandial glycemia, with significant interaction for area
under the curve (AUC). Therefore, it was concluded that
AG reduced postprandial glycemia irrespective of dose and
time of administration (Vuksan et al. 2000b). AG taken at
different times did not have an additional influence on
postprandial glycemia. In nondiabetic individuals, 3, 6, or
9 g of AG taken 40, 80, or 120 min before a glucose
challenge similarly improved glucose tolerance (Vuksan
et al. 2000c). AG also showed enhanced antioxidative and
antihyperglycemic effects. In another study, glycogen and
high density lipoprotein (HDL) content were significantly
increased, while levels of plasma cholesterol and low
density lipoprotein (LDL) were significantly decreased, in
the AG-treated group (Yoo et al. 2012).
Sen et al. investigated the effects of North American
ginseng (NAG) root extract on type 1 and type 2 diabetes
and the mechanisms underlying such effects. NAG reduced
blood glucose and glycated hemoglobin levels in the
groups with type 1 and type 2 diabetes NAG (Sen et al.
2013).
Intraperitoneal injection of an aqueous extract of the
crude drug ‘‘shigoka’’ (Siberian ginseng) remarkably
diminished plasma glucose levels in mice. Activity-guided
fractionation of the extract yielded seven glycans (eleu-
therans A, B, C, D, E, F, and G) that exerted marked
123

hypoglycemic effects in normal and alloxan-induced
hyperglycemic mice (Hikino et al. 1986). Malonyl ginse-
nosides (MGR) are natural ginsenosides found in both fresh
and air-dried ginseng. Administration of MGR to high fat
diet/streptozotocin diabetic rats significantly reduced fast-
ing blood glucose levels, improved glucose tolerance, and
enhanced insulin sensitivity, without affecting body weight
(Liu et al. 2013b).
Mechanism
Data indicate that NAG may produce a protective effect
against diabetes through regeneration of b-cells, which
results in enhanced insulin secretion (Sen et al. 2013).
Treatment with ginseng polysaccharides resulted in a sig-
nificant decrease in serum malondialdehyde levels and sig-
nificant increases in serum insulin, superoxide dismutase
activity, and hepatic glycogen content, and these mecha-
nisms may underlie the anti-diabetic activity of intra-gastric
ginseng polysaccharides (Sun et al. 2014). Ginseng poly-
saccharides affect fasting blood glucose levels by stimulat-
ing insulin secretion to promote glycogen synthesis (Lee
et al. 2012). In addition, ANG increased the expression of
insulin and decreased the expression of uncoupling protein 2,
Bax, and poly ADP-ribose polymerase, which may be the
primary targets of Korean ginseng that result in increased
insulin action and secretion, decreased b-cell mass, and
normalized glucose homeostasis (Kim and Kim 2012).
Panax ginseng appeared to induce CYP3A activity in
the liver and the gastrointestinal tract (Malati et al. 2012).
Ginseng activated CYP3A4 in vitro (Anderson et al. 2003).
Pioglitazone and repaglinide are substrates of CYP3A4.
Importance and management
These studies show that P. ginseng, P. quinquefolius, and
other species of ginseng might possess blood-glucose-
lowering activity, but a multiple-dose study showed that
this effect was not clinically relevant in patients with well-
controlled diabetes (Jellin et al. 2014, Williamson et al.
2013).
Karela
The blood glucose-lowering effects of antidiabetics can be
increased by Karela (Momordica charantia) (Williamson
et al. 2013). Due to its hypoglycemic effect, Karela inter-
acts with conventional anti-diabetics.
Evidence of interaction
One report of a diabetic patient, whose diabetes was poorly
controlled by diet regulation and chlorpropamide, but well
123
S. Rehman et al.
controlled with karela curry, provides some evidence that the
blood glucose-lowering effect of karela and conventional oral
anti-diabetics can be additive (Aslam and Stockley 1979).
Karela produces significant improvement in glucose tolerance
in patients with T2DM when they were taking chlorpropamide
(Leatherdale et al. 1981), tolbutamide (Leatherdale et al. 1981),
glibenclamide (Leatherdale et al. 1981; Tongia et al. 2004),
glymidine (Leatherdale et al. 1981) or metformin (Tongia et al.
2004), as well as when they are not taking antidiabetics (Akhtar
1982; Srivastava et al. 1993; Welihinda et al. 1986). However,
one randomized study showed no significant effect on glycated
hemoglobin (HbA1c) and no change in FBG (Dans et al. 2007).
A case report on two young non-diabetic children reported
hypoglycaemic coma and seizures after they were given karela
tea (Hulin et al. 1988). In an experiment with rats, the combi-
nation of an alcoholic extract of karela with 2 or 5 mg/kg ros-
iglitazone caused a greater reduction in serum glucose levels
than either dose of rosiglitazone alone (Nivitabishekam et al.
2009). The blood glucose-lowering effects of karela may be due
to its bioactive constituent polypeptide P (Khanna et al. 1981),
which is effective when administered subcutaneously (Baldwa
et al. 1977). However, the oral activity of polypeptide P is not
well-characterized (Raman and Lau 1996). Other constituents
of karela with blood glucose-lowering effects include the sterol
glucoside mixture, charantin, which is found in the fruit, and the
pyrimidine nucleoside vicine, which is found in the seeds
(Raman and Lau 1996).
Mechanism
Karela can produce insulin-like effects and stimulate insulin
secretion (Raman and Lau 1996), and thus has additive effect
with conventional antidiabetics. Momordica charantia
inhibited CYP2C9 with IC50 values between 63.4 and
425.9 lg/mL (Appiah-Opong et al. 2008). Raza et al. reported
that changes in hepatic phase I and phase II drug-metabolizing
enzyme activities in streptozotocin (STZ)-induced diabetic
animals may be associated with altered expression of CYP and
glutathione S-transferase (GST) isozymes (Raza et al. 1996,
2000). Glibenclamide, glimepiride, glipizide, nateglinide, and
rosiglitazone are substrates of CYP2C9.
Importance and management
The blood glucose-lowering activity of karela appears to be
established, although the best controlled clinical study on
karela found its effects to be minimal. The aqueous extract
powder of M. charantia, an edible vegetable, appears to be
a safe alternative blood glucose-lowering agent for diabetic
patients (Virdi et al. 2003). Health professionals should
therefore be aware that patients could be using karela, as
well as conventional drugs, to control their diabetes (Jellin
et al. 2014; Williamson et al. 2013).
Interactions between herbs and antidiabetics

Lycium CYP2C8-mediated clearance of rosiglitazone after a single

administration, and the magnitude of the effect of SJW is
Plants of the genus Lycium have also been used in tradi- not influenced by CYP2C8 genotype (Hruska et al. 2005).
tional medicine as treatments for diabetes (Ahmed et al. Consumption of SJW for 14 days had no clinically sig-
2009; Muhammad et al. 2006; Tiwari et al. 2010). nificant effect on the pharmacokinetics and pharmacody-
namics of repaglinide (Fan et al. 2011). Tolbutamide
Evidence of interaction metabolism is not affected by SJW (Arold et al. 2005;
Wang et al. 2001).
Knowledge of the interaction between Lycium and antidi-
abetics is based on experimental evidence only. The extract
Mechanism
of the root bark of Lycium barbarum is known to produce
antidiabetic effects in rabbits that are associated with
SJW extract (containing hyperforin) at low concentrations
reduced blood glucose levels (Ahmed et al. 2009). Lycium
targets key mechanisms of cytokine-induced beta-cell
barbarum polysaccharides (glycoconjugates), containing
injury, thereby improving beta-cell function and survival.
several monosaccharides and 17 amino acids, are major
Thus, SJW may have value as a treatment to prevent or
bioactive constituents that produce hypoglycemic effects.
limit beta-cell loss in diabetes (Menegazzi et al. 2008).
In addition, polysaccharides and vitamin antioxidants from
Adipocytes are insulin-sensitive cells that play a major role
L. barbarum fruits may produce hypolipidemic effects
in energy homeostasis. SJW extracts inhibit adipogenesis
(Luo et al. 2004). The effects of Lycium barbarum poly-
in 3T3-L1 cells and insulin-sensitive glucose uptake in
saccharide (LBP) on improvements in insulin resistance
mature fat cells (Richard et al. 2012). Therefore, the effects
and lipid profiles were studied in a rat model of non-insulin
of SJW are additive with conventional antidiabetics.
dependent diabetes mellitus (NIDDM), and it was found
Long-term SJW administration resulted in a significant
that LBP ameliorated insulin resistance (Zhao et al. 2005).
and selective induction of CYP3A activity in the intestinal
wall (Wang et al. 2001). The SJW constituent hyperforin
Mechanism
activates the pregnane X receptor (PXR) (Moore et al.
2000), which results in increased transcription of CYP3A4
The antidiabetic mechanism of Lycium may involve
and the drug efflux transporter ABCB1 (P-glycoprotein)
increasing levels of GLUT4 at the cell surface, improving
(Hruska et al. 2005). Induction of CYP3A4 and/or ABCB1
GLUT4 trafficking, and enhancing intracellular insulin
increases the metabolism and excretion of drug substrates,
signaling (Zhao et al. 2005). Lycium appears to reduce
eventually leading to decreased systemic exposure and
blood-glucose levels by improving glucose transport and
possibly decreased therapeutic efficacy (Goey et al. 2014).
increasing insulin signaling; therefore, these effects may be
Several in vitro experiments with components of SJW
additive with conventional antidiabetics (Williamson et al.
extracts showed that hyperforin and hypericin influenced
2013). In vitro studies suggest that Lycium may be a weak
enzyme activity differently. Hyperforin markedly inhibited
inhibitor of CYP2C9 (Lam et al. 2001).
the activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6,
and CYP3A4, whereas hypericin inhibited CYP2D6 only
Importance and management
(Obach 2000). Gliclazide is a substrate of CYP2C9, and the
authors suggest that SJW induces this enzyme, thereby
The limited experimental evidence suggests that lycium
increasing the metabolism of gliclazide and reducing its
may have antidiabetic properties, and this finding is sup-
systemic exposure (Xu et al. 2008). Other substrates of
ported by the traditional use of Lycium to treat diabetes.
CYP2C9 include glibenclamide, glimepiride, glipizide,
Therefore, there is a theoretical possibility that lycium may
nateglinide, and rosiglitazone. Pioglitazone and repaglinide
enhance the blood-glucose-lowering effects of conven-
are substrates of CYP3A4.
tional antidiabetics (Williamson et al. 2013).

St. John’s wort Importance and management

Evidence of interaction As mentioned above, SJW extract inhibits CYP2C9 and

Treatment with SJW significantly increases the apparent
clearance of gliclazide and modestly decreases the glicla-
zide AUC, and this effect is independent of CYP2C9
genotype (Xu et al. 2008). SJW also significantly increases
CYP3A4. Therefore, conventional antidiabetics that are
substrates of CYP2C9 and CYP3A4 have significant
pharmacokinetic interactions with SJW. Glibenclamide,
glimepiride, glipizide, nateglinide, and rosiglitazone are
substrates of CYP2C9, whereas pioglitazone and

123
 S. Rehman et al.

Table 3 Micellaneous herbs Interacting Herb–drug Mechanism type References

which may cause interactions herb interactions
with antidiabetic drugs severity
(Williamson
et al. 2013)

Agrimony ?? Pharmacodynamics (insulin-releasing and Ahn et al. (2011), Gray

? Cocoa
For interactions that are not
considered to be of clinical
significance, or where no
interaction occurs
??
For interactions where
there is doubt about the outcome
of concurrent use, and therefore
it may be necessary to give
patients some guidance about
possible adverse effects, and/or
consider some monitoring
???
For interactions where
there is a potentially hazardous
outcome, but where, perhaps,
the data is poor and conclusions
about the interaction are
difficult to draw
insulin-like activity) and Flatt (1998) and
Swanston et al. (1990)
Alfalfa ?? Pharmacodynamics (stimulation of insulin Gray and Flatt (1997)
secretion from the BRIN-BD11)
?? Pharmacodynamics (improve insulin signaling Cordero-Herrera et al.
and modulate glucose uptake) (2013)
Coffee ?? Pharmacodynamics (improve glucose tolerance Van Dam et al. (2004)
and metabolism) and Van Dam (2006)
Elder ?? Pharmacodynamics (enhance insulin secretion, Gray et al. (2000) and
increased 2-deoxy-glucose transport, glucose Williamson et al. (2013)
oxidation and glycogenesis)
Fenugreek ?? Pharmacodynamics (affecting an insulin Williamson et al. (2013)
signaling pathway)
Flaxseed ?? Pharmacodynamics (increase in liver glucose- Dusane and Joshi (2013)
6-phosphate dehydrogenase enzyme activity
and normal glycogenesis, and formation of
new islets)
Holy basil ?? Pharmacodynamics (stimulate and activate Narendhirakannan et al.
insulin) (2006) and Hannan
et al. (2006)

repaglinide are substrates of CYP3A4. Actos, a maker of
pioglitazone, recommends caution when prescribing piog-
litazone with drugs that induce CYP2C8 (Actos, Summary
of product characteristics 2011; Komoroski et al. 2005;
Williamson et al. 2013). The concurrent use of SJW should
be monitored when patients are also given antidiabetic
drugs that are substrates of CYP2C8, CYP2C9, or
CYP3A4. Treatment with SJW significantly increases the
apparent clearance of gliclazide, and this effect is inde-
pendent of CYP2C9 genotype. People with diabetes
receiving this combination should be closely monitored to
evaluate possible signs of reduced efficacy (Xu et al. 2008).
Miscellaneous herbs
Numerous herbs have been traditionally used for the
treatment of diabetes in addition to those described above,
including agrimony, alfalfa, cocoa, coffee, elder, fenu-
greek, flaxseed, and holy basil (Table 3). These herbs may
lead to pharmacodynamic interactions when they are co-
administered with antidiabetic therapeutic drugs due to
their antidiabetic effects, but there is limited clinical and
experimental evidence regarding such interactions. There-
fore, caution should be paid to possible drug interactions
between these herbs and antidiabetic drugs in the context of
diabetic control.
Ingredients derived from herbs or other natural sources
This part deals with possible interactions between several
representative ingredients from herbs or natural products
and antidiabetic drugs, which are summarized in Table 4.
Glucosamine
Evidence of interaction A study by Scroggie et al. pro-
vided evidence that glucosamine-chondroitin supplemen-
tation (glucosamine hydrochloride 1.5 g daily with
chondroitin sulfate sodium 1.2 g daily) for 90 days in
osteoarthritis patients with diabetes does not pose a sig-
nificant risk of worsening glycemic control in the form of
elevated hemoglobin A1c levels (Scroggie et al. 2003). In
2000, the Canadian Adverse Drug Reaction Monitoring
Programme (CADRMP) reported that unexpected increases
in blood-glucose levels had occurred in diabetic patients
taking glucosamine sulfate or glucosamine with chondroi-
tin (Persiani et al. 2009). In one case study, glucosamine
was reported to reduce hypoglycemic episodes in a patient
with metastatic insulinoma (Chan et al. 2001).
Mechanism Endogenous glucosamine plays a role in
glucose metabolism and may increase insulin resistance.
The lack of a negative impact of glucosamine on glycemic

123
Interactions between herbs and antidiabetics

Table 4 Ingredients derived from herbs or other natural sources which may cause interactions with antidiabetic drugs
Interacting Herb–drug Mechanism type Possible interacting References
herb interactions antidiabetic drugs
severity
(Williamson
et al. 2013)

Glucosamine ??? Pharmacodynamics (glucose metabolism, No specification Chan et al. (2001) and
increase insulin resistance; endogenous insulin Jain and McCormick
secretion in response to a possible increase in (2004)
insulin resistance)
Isoflavones ?? Pharmacokinetics (CYP2C9 and CYP3A4) Glibenclamide, glimepiride, Guo et al. (2014), Chen
Pharmacodynamics (activate a1-adrenoceptors to glipizide, nateglinide, et al. (2004), Hsu et al.
enhance the secretion of b-endorphin, decrease rosiglitazone, pioglitazone, (2003) and Fu et al.
of plasma glucose; increased glucose repaglinide (2006)
transporter (GLUT4), and preventing islet cells)
Levocarnitine ?? Pharmacokinetics (CYP2C9 and CYP3A4) Glibenclamide, glimepiride, Guo et al. (2014) and
Pharmacodynamics (depressed in the insulin glipizide, nateglinide, Mingrone et al. (1999)
resistant by activation of pyruvate rosiglitazone, pioglitazone,
dehydrogenase) repaglinide
?
For interactions that are not considered to be of clinical significance, or where no interaction occurs
??
For interactions where there is doubt about the outcome of concurrent use, and therefore it may be necessary to give patients some guidance
about possible adverse effects, and/or consider some monitoring
???
For interactions where there is a potentially hazardous outcome, but where, perhaps, the data is poor and conclusions about the interaction
are difficult to draw

control may be due to increased insulin resistance (Jellin
et al. 2014).
Importance and management The effect of glucosamine
on glycemic control in patients at an early stage in the
course of diabetes may be explained by a compensatory
increase in endogenous insulin secretion in response to a
possible increase in insulin resistance. These results may
not hold true in patients in a later stage of the disease, who
may lack the ability to compensate for the effects of glu-
cosamine because of their inability to increase insulin
secretion. Confirmation of these results in a wider spectrum
of diabetic patients could validate glucosamine as an
osteoarthritis treatment option (Jain and McCormick 2004).
Therefore, it may be prudent to increase monitoring of
blood-glucose in patients if glucosamine supplements are
taken (Jellin et al. 2014; Williamson et al. 2013).
Isoflavones
Evidence of interaction Knowledge of the interaction
between isoflavones and antidiabetics is based on experi-
mental evidence only. Puerarin at a dose that lowered
plasma glucose increased plasma b-endorphin-like immu-
noreactivity (BER) in STZ-induced diabetic rats (Chen
et al. 2004). In another study, a bolus intravenous injection
of puerarin decreased plasma glucose concentrations in a
dose-dependent manner in STZ-induced diabetic rats. In
this study, puerarin at a dose of 15.0 mg/kg significantly
attenuated the increase in plasma glucose induced by an
intravenous glucose challenge in normal rats. In the iso-
lated soleus muscle of STZ-induced diabetic rats, puerarin
enhanced the uptake of radioactive glucose in a concen-
tration-dependent manner. Moreover, mRNA and protein
levels of GLUT4 in soleus muscle were increased after
repeated intravenous administration of puerarin in STZ-
induced diabetic rats for 3 days (Hsu et al. 2003).
Mechanism The pharmacokinetic interactions of puerarin
with antidiabetics in rats are mediated by its inhibitory
effects on CYP2C9 and CYP3A4 activities (Guo et al.
2014). Puerarin may also activate a1-adrenoceptors in the
adrenal gland to enhance the secretion of b-endorphin
(Chen et al. 2004). Liang et al. suggest that puerarin pro-
tects islet cells against oxidative stress by stimulating the
activities of antioxidant enzymes. Moreoever, puerarin
may protect islet cells from the toxic action of reactive
oxygen species in diabetes (Fu et al. 2006).
Importance and required management Isoflavones might
have additive effects when they are combined with anti-
diabetic drugs, and thus antidiabetic doses might need to be
adjusted. Furthermore, due to the inhibitory effects of
puerarin rat CYP2C9 and CYP3A4 enzyme activities,

123

puerarin interacts with antidiabetics that are substrates of
these enzymes (Guo et al. 2014). Glibenclamide, glimepi-
ride, glipizide, nateglinide, and rosiglitazone are substrates
of CYP2C9. Pioglitazone and repaglinide are substrates of
CYP3A4.
Levocarnitine
Carnitine derivatives have been tested in patients with
diabetes for a variety of indications, including treatment of
diabetic neuropathy and improvement in lipid profiles
(Williamson et al. 2013), as well as to try to improve
insulin sensitivity. Due to its hypoglycemic effect, carni-
tine interacts with conventional anti-diabetics.
Evidence of interaction Rahbar et al. investigated the
effects of oral L-carnitine administration on fasting plasma
glucose (FPG), HbA1c, and lipid parameters to evaluate its
effect on insulin sensitivity and lipid profiles in subjects
with T2DM taking metformin or glibenclamide (glybu-
ride). In patients with T2DM, oral L-carnitine (1 g
administered 3 times daily for 12 weeks) significantly
lowered FPG, but increased fasting triglyceride levels
(Rahbar et al. 2005).
In a randomized, placebo-controlled study in patients
with T2DM not taking any antidiabetic medications, oral L-
carnitine administration (1 g administered 3 times daily
before meals for 4 weeks) had no effect on insulin sensi-
tivity or lipid profiles (Gonzalez-Ortiz et al. 2008). Con-
stant infusion of L-carnitine improved insulin sensitivity in
insulin resistant diabetic patients, and a significant effect
on whole body insulin-mediated glucose uptake was
observed in normal subjects (Mingrone et al. 1999). In
patients with poorly controlled diabetes taking oral antid-
iabetics or insulin, treatment with oral L-carnitine (2 g
daily) and either sibutramine (10 mg) or orlistat slightly
improved diabetic control in comparison with sibutramine
or orlistat alone (Derosa et al. 2010a, b).
Mechanism In diabetic patients taking L-carnitine, glu-
cose taken up by the tissues appears to be promptly utilized
as fuel, because glucose oxidation is increased during L-
carnitine administration. Significantly reduced plasma
levels of lactate after L-carnitine administration suggest
that this effect might be exerted through pyruvate dehy-
drogenase activation, which is depressed in patients with
insulin resistance (Mingrone et al. 1999).
Importance and management The clinical evidence dis-
cussed above indicates that, in most patients with diabetes,
oral L-carnitine has little effect on diabetic control, and
prominent hypoglycemia does not appear to have been
reported. However, giving L-carnitine to diabetic patients
123
S. Rehman et al.
receiving insulin or oral antidiabetics might result in
hypoglycemia, and regular monitoring of plasma glucose
concentrations in these patients may be required.
Conclusion
As herbal therapies are increasingly being used around the
world because they are perceived to be free of side effects,
it is important to be aware of their possible harm and herb–
drug interactions. The solution for this trend is not to avoid
or suppress the use of herbal medicines, but rather to
induce rational, safe, and effective use. Furthermore, it may
be desirable to apply safe adjunctive treatment or co-
administration of herbal medicines with prescription med-
ication in some conditions where separate use of conven-
tional drugs seems to be inappropriate. Therefore, it is
necessary to educate practitioners and consumers on the
importance of herb–drug interactions and appropriate
treatment management. Ideal treatment strategies for her-
bal therapy could be achieved based on a complete bio-
logical and clinical database for natural products, as well as
its standardization. However, clinical and experimental
data on herb–drug interactions, including antidiabetic-herb
interactions, is limited, and attention must be focused on
collecting and preserving clinical evidence and performing
experiments using animal models. Therefore, more
research should be conducted to ensure rational use of
herbal medicines both alone and in combination with
conventional medicines.
Owing to different comorbidities, diabetes patients are
often treated with multiple medications in a practice
referred to as polypharmacotherapy, which is especially
common in the elderly (Caughey et al. 2010). As these
medications are used for the duration of their lives by this
patient group, they are at increased risk of harmful herb–
drug interactions and drug–drug interactions. These inter-
actions could produce acute hypoglycemic/hyperglycemic
conditions that require emergency management. For these
reasons, particular attention should be paid to interactions
of herbs with anti-diabetic drugs.
Acknowledgments This work was supported by the research fund
of Hanyang University (HY-2013-G).
References
Actos (Pioglitazone hydrochloride). 2011. UK summary of product
characteristics. London: Takeda Ltd.
Ahmed, M., A. Alamgeer, T. Sharif, C.H. Zabta, and A. Akbar. 2009.
Effect of Berberis lycium Royle on lipid profile in alloxan
induced diabetic rabbits. Ethnobotanical Leaflets 13: 702–708.
Ahn, E.K., J.A. Lee, D.W. Seo, S.S. Hong, and J.S. Oh. 2011. 1b-
Hydroxy-2-oxopomolic acid isolated from Agrimonia pilosa
Interactions between herbs and antidiabetics
extract inhibits adipogenesis in 3T3-L1 cells. Biological &
Pharmaceutical Bulletin 35: 643–649.
Akhtar, M. 1982. Trial of Momordica charantia Linn (Karela) powder
in patients with maturity-onset diabetes. The Journal of the
Pakistan Medical Association 32: 106–107.
Al-Ali, M., S. Wahbi, H. Twaij, and A. Al-Badr. 2003. Tribulus
terrestris: Preliminary study of its diuretic and contractile effects
and comparison with Zea mays. Journal of Ethnopharmacology
85: 257–260.
Ali, M.A., H.A. Sagar, M.C.S. Khatun, A.K. Azad, K. Begum, and
M.I.I. Wahed. 2012. Antihyperglycemic and analgesic activities
of ethanolic extract of Cassia fistula (L.) stem bark. Interna-
tional Journal of Pharmaceutical Sciences and Research 3:
416–423.
Amacher, D.E. 2010. The effects of cytochrome P450 induction by
xenobiotics on endobiotic metabolism in pre-clinical safety
studies. Toxicology Mechanisms and Methods 20: 159–166.
Anderson, G.D., G. Rosito, M.A. Mohustsy, and G.W. Elmer. 2003.
Drug interaction potential of soy extract and Panax ginseng. The
Journal of Clinical Pharmacology 43: 643–648.
Anthony, J.B., and C.M. Gregory. Pharmacology Weekly.
Retrieved June 2014, from http://www.pharmacologyweekly.
com/content/pages/cytochrome-cyp-p450-enzyme-medication-
herbs-substrates.
Appiah-Opong, R., J.N. Commandeur, C. Axson, and N.P. Verme-
ulen. 2008. Interactions between cytochromes P450, glutathione
S-transferases and Ghanaian medicinal plants. Food and Chem-
ical Toxicology 46: 3598–3603.
Arold, G., F. Donath, A. Maurer, K. Diefenbach, S. Bauer, H.H.
Henneicke-Von Zepelin, M. Friede, and I. Roots. 2005. No
relevant interaction with alprazolam, caffeine, tolbutamide, and
digoxin by treatment with a low-hyperforin St. John’s wort
extract. Planta Medica 71: 331–337.
Asdaq, S.M.B., and M.N. Inamdar. 2010. Pharmacodynamic interac-
tion of captopril with garlic in isoproterenol-induced myocardial
damage in rat. Phytotherapy Research 24: 720–725.
Aslam, M., and I. Stockley. 1979. Interaction between curry
ingredient (karela) and drug (chlorpropamide). The Lancet 313:
607.
Baldwa, V., C. Bhandari, A. Pangaria, and R. Goyal. 1977. Clinical
trial in patients with diabetes mellitus of an insulin-like
compound obtained from plant source. Upsala Journal of
Medical Sciences 82: 39–41.
Beckert, B.W., M.J. Concannon, S.L. Henry, D.S. Smith, and C.L.
Puckett. 2007. The effect of herbal medicines on platelet
function: an in vivo experiment and review of the literature.
Plastic and Reconstructive Surgery 120: 2044–2050.
Bent, S., H. Goldberg, A. Padula, and A.L. Avins. 2005. Spontaneous
bleeding associated with Ginkgo biloba. Journal of General
Internal Medicine 20: 657–661.
Bertram, G.K. 2012. Basic and clinical pharmacology. New York:
Editorial Mc Graw Hill.
Borhanuddin, M., M. Shamsuzzoha, and A.H. Hussain. 1994.
Hypoglycemia effects of Andrographis paniculata Nees on
non-diabetic rabbits. Bangladesh Medical Research Council
Bulletin 20: 2–24.
Boullata, J. 2005. Natural health product interactions with medica-
tion. Nutrition in Clinical Practice 20: 33–51.
Brown, L., O. Heyneke, D. Brown, J. Van Wyk, and J. Hamman.
2008. Impact of traditional medicinal plant extracts on antiret-
roviral drug absorption. Journal of Ethnopharmacology 119:
588–592.
Budzinski, J., B. Foster, S. Vandenhoek, and J. Arnason. 2000. An
in vitro evaluation of human cytochrome P450 3A4 inhibition by
selected commercial herbal extracts and tinctures. Phytomedi-
cine 7: 273–282.
Budzinski, J.W., V.L. Trudeau, C.E. Drouin, M. Panahi, J.T. Arnason,
and B.C. Foster. 2007. Modulation of human cytochrome P450
3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell
monolayers by selected commercial-source milk thistle and
goldenseal products This article is one of a selection of papers
published in this special issue (part 1 of 2) on the Safety and
Efficacy of Natural Health Products. Canadian Journal of
Physiology and Pharmacology 85: 966–978.
Bunyapraphatsara, N., S. Yongchaiyudha, V. Rungpitarangsi, and O.
Chokechaijaroenporn. 1996. Antidiabetic activity of Aloe vera L.
juice II. Clinical trial in diabetes mellitus patients in combination
with glibenclamide. Phytomedicine 3: 245–248.
Butterweck, V., and H. Derendorf. 2008. Potential of pharmacokinetic
profiling for detecting herbal interactions with drugs. Clinical
Pharmacokinetics 47: 383–397.
Cermak, R., and S. Wolffram. 2006. The potential of flavonoids to
influence drug metabolism and pharmacokinetics by local
gastrointestinal mechanisms. Current Drug Metabolism 7:
729–744.
Chan, N.N., S.E. Baldeweg, T.M. Tan, and S.J. Hurel. 2001. Gluco-
samine sulphate and osteoarthritis. The Lancet 357: 1618–1619.
Chatterjee, P., and M.R. Franklin. 2003. Human cytochrome P450
inhibition and metabolic-intermediate complex formation by
goldenseal extract and its methylenedioxyphenyl components.
Drug Metabolism and Disposition 31: 1391–1397.
Caughey, G.E., E.E. Roughead, A.I. Vitry, R.A. McDermott, S.
Shakib, and A.L. Gilbert. 2010. Comorbidity in the elderly with
diabetes: Identification of areas of potential treatment conflicts.
Diabetes Research and Clinical Practice 87: 385–393.
Chavez, M.L., M.A. Jordan, and P.I. Chavez. 2006. Evidence-based
drug–herbal interactions. Life Sciences 78: 2146–2157.
Chen, W.C., S. Hayakawa, T. Yamamoto, H.C. Su, I.M. Liu, and J.T.
Cheng. 2004. Mediation of b-endorphin by the isoflavone
puerarin to lower plasma glucose in streptozotocin-induced
diabetic rats. Planta Medica 70: 113–116.
Choi, J.S., B.W. Jo, and Y.C. Kim. 2004. Enhanced paclitaxel
bioavailability after oral administration of paclitaxel or prodrug
to rats pretreated with quercetin. European Journal of Pharma-
ceutics and Biopharmaceutics 57: 313–318.
Cho, W., W.S. Chung, S.K. Lee, A.W. Leung, C.H. Cheng, and K.K.
Yue. 2006. Ginsenoside Re of Panax ginseng possesses signif-
icant antioxidant and antihyperlipidemic efficacies in streptozo-
tocin-induced diabetic rats. European Journal of Pharmacology
550: 173–179.
Choi, H.C., S.J. Kim, K.Y. Son, B.J. Oh, and B.L. Cho. 2013.
Metabolic effects of aloe vera gel complex in obese prediabetes
and early non-treated diabetic patients: Randomized controlled
trial. Nutrition 29: 1110–1114.
Choudhary, M., A. Kochhar, and J. Sangha. 2014. Hypoglycemic and
hypolipidemic effect of Aloe vera L. in non-insulin dependent
diabetics. Journal of Food Science and Technology 51: 90–96.
Cordero-Herrera, I., M.A. Martı́n, L. Bravo, L. Goya, and S. Ramos.
2013. Cocoa flavonoids improve insulin signalling and modu-
lateglucose production via AKT and AMPK in HepG2 cells.
Molecular Nutrition and Food Research 57: 974–985.
Crosby, E.C., R.L. Dolan, J.E. Benson, M.J. Luetkemeier, R.G.
Barton, and E.W. Askew. 2001. Herbal diuretic induced
dehydration and resting metabolic rate. Medicine and Science
in Sports and Exercise 33: S163.
Daisy, P., K. Balasubramanian, M. Rajalakshmi, J. Eliza, and J.
Selvaraj. 2010. Insulin mimetic impact of Catechin isolated from
Cassia fistula on the glucose oxidation and molecular mecha-
nisms of glucose uptake on streptozotocin-induced diabetic
Wistar rats. Phytomedicine 17: 28–36.
Dans, A.M., M.V. Villarruz, C.A. Jimeno, M.A. Javelosa, J. Chua, R.
Bautista, and G.G. Velez. 2007. The effect of Momordica
123

charantia capsule preparation on glycemic control in Type 2
diabetes mellitus needs further studies. Journal of Clinical
Epidemiology 60: 554–559.
Dasgupta, A., L. Kidd, B.J. Poindexter, and R.J. Bick. 2010. Interfer-
ence of hawthorn on serum digoxin measurements by immuno-
assays and pharmacodynamic interaction with digoxin. Archives
of Pathology and Laboratory Medicine 134: 1188–1192.
Derosa, G., P. Maffioli, S. At Salvadeo, I. Ferrari, A. Gravina, R.
Mereu, A. D’angelo, I. Palumbo, S. Randazzo, and A. Fg Cicero.
2010a. Sibutramine and L-carnitine compared to sibutramine
alone on insulin resistance in diabetic patients. Internal Medicine
49: 1717–1725.
Derosa, G., P. Maffioli, I. Ferrari, A. D’angelo, E. Fogari, I. Palumbo,
S. Randazzo, and A. Cicero. 2010b. Orlistat and L-carnitine
compared to orlistat alone on insulin resistance in obese diabetic
patients. Endocrine Journal 57: 777.
Djuv, A., and O.G. Nilsen. 2012. Aloe vera juice: IC50 and dual
mechanistic inhibition of CYP3A4 and CYP2D6. Phytotherapy
Research 26: 445–451.
Dusane, M.B., and B.N. Joshi. 2013. Beneficial effect of flax seeds in
streptozotocin (STZ) induced diabetic mice: isolation of active
fraction having islet regenerative and glucosidase inhibitory
properties. Canadian Journal of Physiology and Pharmacology
91: 325–331.
Etheridge, A.S., S.R. Black, P.R. Patel, J. So, and J.M. Mathews.
2007. An in vitro evaluation of cytochrome P450 inhibition and
P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape
seed, milk thistle, and ginseng extracts and their constituents.
Planta Medica 73: 731–741.
Fan, L., X.Q. Mao, G.Y. Tao, G. Wang, F. Jiang, Y. Chen, Q. Li, W.
Zhang, H.P. Lei, and D.L. Hu. 2009a. Effect of Schisandra
chinensis extract and Ginkgo biloba extract on the pharmacoki-
netics of talinolol in healthy volunteers. Xenobiotica 39: 249–254.
Fan, L., G.Y. Tao, G. Wang, Y. Chen, W. Zhang, Y.J. He, Q. Li, H.P.
Lei, F. Jiang, and D.L. Hu. 2009b. Effects of Ginkgo biloba
extract ingestion on the pharmacokinetics of talinolol in healthy
Chinese volunteers. Annals of Pharmacotherapy 43: 944–949.
Fan, L., G. Zhou, D. Guo, Y.L. Liu, W.Q. Chen, Z.Q. Liu, Z.R. Tan,
D. Sheng, H.H. Zhou, and W. Zhang. 2011. The pregnane X
receptor agonist St. John’s Wort has no effects on the
pharmacokinetics and pharmacodynamics of repaglinide. Clin-
ical Pharmacokinetics 50: 605–611.
Fetrow, C.W., J.R. Avila, C.W. Fetrow, 1999. Fetrow, and Avila
professional’s handbook of complementary and alternative
medicines. Springhouse, PA: Springhouse Corporation.
Foster, B.C., M.S. Foster, S. Vandenhoek, A. Krantis, J.W. Budzinski,
J.T. Arnason, K.D. Gallicano, and S. Choudri. 2001. An in vitro
evaluation of human cytochrome P450 3A4 and P-glycoprotein
inhibition by garlic. J Pharm Pharm Sci 4: 176–184.
Fu, L.X., H.S. Xia, G. Lu, L.Y. Xiang, and B.X. Hui. 2006. Puerarin
protects rat pancreatic islets from damage by hydrogen peroxide.
European Journal of Pharmacology 529: 1–7.
Gaede, P., H. Lund-Andersen, H.H. Parving, and O. Pedersen. 2008.
Effect of a multifactorial intervention on mortality in type 2
diabetes. New England Journal of Medicine 358: 580–591.
Gaudineau, C., R. Beckerman, S. Welbourn, and K. Auclair. 2004.
Inhibition of human P450 enzymes by multiple constituents of
the Ginkgo biloba extract. Biochemical and Biophysical
Research Communications 318: 1072–1078.
Gilbert, G.J. 1997. Ginkgo biloba. Neurology 48: 1137-1137.
Goey, A.K., I. Meijerman, H. Rosing, S. Marchetti, M. Mergui-
Roelvink, M. Keessen, J.A. Burgers, J.H. Beijnen, and J.H.
Schellens. 2014. The effect of St. John’s Wort on the pharma-
cokinetics of docetaxel. Clinical Pharmacokinetics 53: 103–110.
123
S. Rehman et al.
Gonzalez-Ortiz, M., S.O. Hernandez-Gonzalez, E. Hernández-
Salazar, and E. Martı́nez-Abundis. 2008. Effect of oral L-
carnitine administration on insulin sensitivity and lipid profile in
type 2 diabetes mellitus patients. Annals of Nutrition &
Metabolism 52: 335–338.
Gorski, J.C., S.M. Huang, A. Pinto, M.A. Hamman, J.K. Hilligoss,
N.A. Zaheer, M. Desai, M. Miller, and S.D. Hall. 2004. The
effect of echinacea (Echinacea purpurea root) on cytochrome
P450 activity in vivo. Clinical Pharmacology and Therapeutics
75: 89–100.
Gray, A.M., Y.H. Abdel-Wahab, and P.R. Flatt. 2000. The traditional
plant treatment, Sambucus nigra (elder), exhibits insulin-like and
insulin-releasing actions in vitro. The Journal of Nutrition 130:
15–20.
Gray, A.M., and P.R. Flatt. 1997. Pancreatic and extra-pancreatic
effects of the traditional anti-diabetic plant, Medicago sativa
(lucerne). British Journal of Nutrition 78: 325–334.
Gray, A.M., and P.R. Flatt. 1998. Actions of the traditional anti-
diabetic plant, Agrimony eupatoria (agrimony): effects on
hyperglycaemia, cellular glucose metabolism and insulin secre-
tion. British Journal of Nutrition 80: 109–114.
Greenblatt, D.J., L.L. Moltke, Y. Luo, E.S. Perloff, K.A. Horan, A.
Bruce, R.C. Reynolds, J.S. Harmatz, B. Avula, and I.A. Khan.
2006. Ginkgo biloba does not alter clearance of flurbiprofen, a
cytochrome P450-2C9 substrate. The Journal of Clinical Phar-
macology 46: 214–221.
Guo, Y.J., D.L. Liang, Z.S. Xu, and Q. Ye. 2014. In vivo inhibitory
effects of puerarin on selected rat cytochrome P450 isoenzymes.
Die Pharmazie-An International Journal of Pharmaceutical
Sciences 69: 367–370.
Gurley, B.J., S.F. Gardner, M.A. Hubbard, D.K. Williams, W.B.
Gentry, I.A. Khan, and A. Shah. 2005. In vivo effects of
Goldenseal, kava kava, black cohosh, and valerian on human
cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes.
Clinical Pharmacology and Therapeutics 77: 415–426.
Gurley, B.J., A. Swain, M.A. Hubbard, D.K. Williams, G. Barone, F.
Hartsfield, Y. Tong, D.J. Carrier, S. Cheboyina, and S.K. Battu.
2008. Clinical assessment of CYP2D6-mediated herb–drug
interactions in humans: Effects of milk thistle, black cohosh,
goldenseal, kava kava, St. John’s Wort, and Echinacea. Molec-
ular Nutrition & Food Research 52: 755–763.
Hafner-Blumenstiel, V. 2011. Herbal drug–drug interaction and
adverse drug reactions. Therapeutische Umschau. Revue Thér-
apeutique 68: 54.
Hannan, J., L. Marenah, L. Ali, B. Rokeya, P. Flatt, and Y. Abdel-
Wahab. 2006. Ocimum sanctum leaf extracts stimulate insulin
secretion from perfused pancreas, isolated islets and clonal
pancreatic b-cells. Journal of Endocrinology 189: 127–136.
Hellum, B.H., Z. Hu, and O.G. Nilsen. 2007. The induction of
CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in
cultured primary human hepatocytes. Basic & Clinical Pharma-
cology & Toxicology 100: 23–30.
Hikino, H., M. Takahashi, K. Otake, and C. Konno. 1986. Isolation
and hypoglycemic activity of eleutherans A, B, C, D, E, F, and
G: Glycans of Eleutherococcus senticosus roots. Journal of
Natural Products 49: 293–297.
Hiratsuka, M. 2012. In vitro assessment of the allelic variants of
cytochrome P450. Drug Metabolism and Pharmacokinetics 27:
68–84.
Hou, X.L., K. Takahashi, N. Kinoshita, F. Qiu, K. Tanaka, K.
Komatsu, K. Takahashi, and J. Azuma. 2007. Possible inhibitory
mechanism of Curcuma drugs on CYP3A4 in 1a, 25 di-
hydroxyvitamin D-3 treated Caco-2 cells. International Journal
of Pharmaceutics 337: 169–177.
Interactions between herbs and antidiabetics
Hruska, M., J. Cheong, T. Langaee, and R. Frye. 2005. Effect of St.
John’s Wort administration on CYP2C8 mediated rosiglitazone
metabolism. Clinical Pharmacology and Therapeutics 77: P35.
Hsu, F.L., I.M. Liu, D.H. Kuo, W.C. Chen, H.C. Su, and J.T. Cheng.
2003. Antihyperglycemic effect of puerarin in streptozotocin-
induced diabetic rats. Journal of Natural Products 66: 788–792.
Hulin, A., M. Wavelet, and J. Desbordes. 1988. Intoxication aiguë par
Momordica charantia (Sorrossi)(à propos de deux cas). Médecine
d’Afrique Noire 35: 671–674.
Isnard Bagnis, C., G. Deray, A. Baumelou, M. Le Quintrec, and J.L.
Vanherweghem. 2004. Herbs and the kidney. American Journal
of Kidney Diseases 44: 1–11.
Izzo, A.A., and E. Ernst. 2009. Interactions between herbal medicines
and prescribed drugs. Drugs 69: 1777–1798.
Jain, R.K., and J.C. Mccormick. 2004. Can glucosamine supplements
be applied for all patients with type 2 diabetes with osteoarthri-
tis? Archives of Internal Medicine 164: 807.
Jellin, J., P. Gregory, F. Batz, and R. Bonakdar. 2014. Natural
medicines comprehensive database. Stockton, CA: Therapeutic
Research Faculty.
Jiang, X., E.Y. Blair, and A.J. Mclachlan. 2006. Investigation of the
effects of herbal medicines on warfarin response in healthy
subjects: A population pharmacokinetic-pharmacodynamic mod-
eling approach. The Journal of Clinical Pharmacology 46:
1370–1378.
Kang, M.H., and H.M. Park. 2010. Hypertension after ingestion of
baked garlic (Allium sativum) in a dog. The Journal of
Veterinary Medical Science/The Japanese Society of Veterinary
Science 72: 515.
Karyekar, C., N. Eddington, and T. Dowling. 2002. Effect of St.
John’s Wort extract on intestinal expression of cytochrome
P4501A2: studies in LS180 cells. Journal of Postgraduate
Medicine 48: 97.
Khanna, P., S. Jain, A. Panagariya, and V. Dixit. 1981. Hypoglycemic
activity of polypeptide-p from a plant source. Journal of Natural
Products 44: 648–655.
Kim, B.H., K.P. Kim, K.S. Lim, J.R. Kim, S.H. Yoon, J.Y. Cho, Y.O.
Lee, K.H. Lee, I.J. Jang, and S.G. Shin. 2010. Influence of
Ginkgo biloba extract on the pharmacodynamic effects and
pharmacokinetic properties of ticlopidine: An open-label, ran-
domized, two-period, two-treatment, two-sequence, single-dose
crossover study in healthy Korean male volunteers. Clinical
Therapeutics 32: 380–390.
Kim, D.Y., H.D. Yuan, I.K. Chung, and S.H. Chung. 2009.
Compound K, intestinal metabolite of ginsenoside, attenuates
hepatic lipid accumulation via AMPK activation in human
hepatoma cells. Journal of Agricultural and Food Chemistry 57:
1532–1537.
Kim, H.Y., and K. Kim. 2012. Regulation of signaling molecules
associated with insulin action, insulin secretion and pancreatic b-
cell mass in the hypoglycemic effects of Korean red ginseng in
Goto-Kakizaki rats. Journal of Ethnopharmacology 142: 53–58.
Kim, I.S., S.Y. Kim, and H.H. Yoo. 2012. Effects of an aqueous-
ethanolic extract of ginger on cytochrome P450 enzyme-
mediated drug metabolism. Pharmazie 67: 1007–1009.
Kim, K.A., P.W. Park, H.K. Kim, J.M. Ha, and J.Y. Park. 2005. Effect
of quercetin on the pharmacokinetics of rosiglitazone, a CYP2C8
substrate, in healthy subjects. The Journal of Clinical Pharma-
cology 45: 941–946.
Kober, M., K. Pohl, and T. Efferth. 2008. Molecular Mechanisms
Underlying St. Johns wort Drug Interactions. Current Drug
Metabolism 9: 1027–1037.
Komoroski, B.J., R.A. Parise, M.J. Egorin, S.C. Strom, and R.
Venkataramanan. 2005. Effect of the St. John’s wort constituent
hyperforin on docetaxel metabolism by human hepatocyte
cultures. Clinical Cancer Research 11: 6972–6979.
Kuhn, M.A. 2002. Herbal remedies: Drug–herb interactions. Critical
Care Nurse 22: 22–32.
Lai, D.M., Y.K. Tu, I.M. Liu, and J.T. Cheng. 2006. Mediation of
beta-endorphin by ginsenoside Rh2 to lower plasma glucose in
streptozotocin-induced diabetic rats. Planta Medica 72: 9–13.
Lam, A.Y., G.W. Elmer, and M.A. Mohutsky. 2001. Possible
interaction between warfarin and Lycium barbarum L. Annals
of Pharmacotherapy 35: 1199–1201.
Langhammer, A.J., and O.G. Nilsen. 2014. In vitro Inhibition of
Human CYP1A2, CYP2D6, and CYP3A4 by six herbs com-
monly used in pregnancy. Phytotherapy Research 28: 603–610.
Leatherdale, B., R. Panesar, G. Singh, T. Atkins, C. Bailey, and A.
Bignell. 1981. Improvement in glucose tolerance due to
Momordica charantia (karela). British Medical Journal (Clinical
Research ed.) 282: 1823.
Lee, M.S., J.T. Hwang, S.H. Kim, S. Yoon, M.S. Kim, H.J. Yang, and
D.Y. Kwon. 2010. Ginsenoside Rc, an active component of
Panax ginseng, stimulates glucose uptake in C2C12 myotubes
through an AMPK-dependent mechanism. Journal of Ethno-
pharmacology 127: 771–776.
Lee, S.H., S.W. Lim, Y.M. Lee, H.S. Lee, and D.K. Kim. 2012.
Polysaccharide isolated from Triticum aestivum stimulates
insulin release from pancreatic cells via the ATP-sensitive K?
channel. International Journal of Molecular Medicine 29: 913.
Lee, W.K., S.T. Kao, I.M. Liu, and J.T. Cheng. 2006. Increase of
insulin secretion by ginsenoside Rh2 to lower plasma glucose in
Wistar rats. Clinical and Experimental Pharmacology and
Physiology 33: 27–32.
Li, W., M. Zhang, V.J. Gu, Z.J. Meng, L.C. Zhao, Y.N. Zheng, L.
Chen, and G.L. Yang. 2012. Hypoglycemic effect of proto-
panaxadiol-type ginsenosides and compound K on Type 2
diabetes mice induced by high-fat diet combining with strepto-
zotocin via suppression of hepatic gluconeogenesis. Fitoterapia
83: 192–198.
Liu, C., M. Zhang, M.Y. Hu, H.F. Guo, J. Li, Y.L. Yu, S. Jin, X.T.
Wang, L. Liu, and X.D. Liu. 2013a. Increased glucagon-like
peptide-1 secretion may be involved in antidiabetic effects of
ginsenosides. Journal of Endocrinology 217: 185–196.
Liu, Z., W. Li, X. Li, M. Zhang, L. Chen, Y.N. Zheng, G.Z. Sun, and
C.C. Ruan. 2013b. Antidiabetic effects of malonyl ginsenosides
from Panax ginseng on type 2 diabetic rats induced by high-fat
diet and streptozotocin. Journal of Ethnopharmacology 145:
233–240.
Luo, Q., Y. Cai, J. Yan, M. Sun, and H. Corke. 2004. Hypoglycemic
and hypolipidemic effects and antioxidant activity of fruit
extracts from Lycium barbarum. Life Sciences 76: 137–149.
Ma, X., C. Zheng, L. Han, B. Xie, J. Jia, Z. Cao, Y. Li, and Y. Chen.
2009. Synergistic therapeutic actions of herbal ingredients and
their mechanisms from molecular interaction and network
perspectives. Drug Discovery Today 14: 579–588.
Madabushi, R., B. Frank, B. Drewelow, H. Derendorf, and V.
Butterweck. 2006. Hyperforin in St. John’s wort drug interac-
tions. European Journal of Clinical Pharmacology 62: 225–233.
Malati, C.Y., S.M. Robertson, J.D. Hunt, C, Chairez, R.M. Alfaro,
J.A. Kovacs, and S.R. Penzak. 2012. Influence of Panax ginseng
on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp)
activity in healthy participants. Journal of Clinical Pharmacol-
ogy 52:932–939.
Malpani, S.N., K.P. Manjunath, H. Sholapur, R.V. Savadi, K.S. Akki,
and S.S. Darade. 2010. Antidiabetic activity of Cassia fistula
Linn. bark in alloxan induced diabetic rats. International Journal
of Pharmaceutical Sciences and Research 2: 382–385.
Marchetti, S., R. Mazzanti, J.H. Beijnen, and J.H. Schellens. 2007.
Concise review: clinical relevance of drug–drug and herb–drug
interactions mediated by the ABC transporter ABCB1 (MDR1,
P-glycoprotein). The Oncologist 12: 927–941.
123

Matsuda, K., Y. Nishimura, N. Kurata, M. Iwase, and H. Yasuhara.
2007. Effects of continuous ingestion of herbal teas on intestinal
CYP3A in the rat. Journal of Pharmacological Sciences 103:
214–221.
Meijerman, I., J.H. Beijnen, and J.H. Schellens. 2006. Herb–drug
interactions in oncology: Focus on mechanisms of induction. The
Oncologist 11: 742–752.
Menegazzi, M., M. Novelli, P. Beffy, V. D’Aleo, E. Tedeschi, R.
Lupi, E. Zoratti, P. Marchetti, H. Suzuki, and P. Masiello. 2008.
Protective effects of St. John’s wort extract and its component
hyperforin against cytokine-induced cytotoxicity in a pancreatic
b-cell line. The International Journal of Biochemistry and Cell
Biology 40: 1509–1521.
Mingrone, G., A.V. Greco, E. Capristo, G. Benedetti, A. Giancaterini,
A.D. Gaetano, and G. Gasbarrini. 1999. L-Carnitine improves
glucose disposal in type 2 diabetic patients. Journal of the
American College of Nutrition 18: 77–82.
Mohutsky, M.A., G.D. Anderson, J.W. Miller, and G.W. Elmer. 2006.
Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro
and in vivo. American Journal of Therapeutics 13: 24–31.
Moltke, L.L., J.L. Weemhoff, E. Bedir, I.A. Khan, J.S. Harmatz, P.
Goldman, and D.J. Greenblatt. 2004. Inhibition of human
cytochromes P450 by components of Ginkgo biloba. Journal
of Pharmacy and Pharmacology 56: 1039–1044.
Moore, L.B., B. Goodwin, S.A. Jones, G.B. Wisely, C.J. Serabjit-
Singh, T.M. Willson, J.L. Collins, and S.A. Kliewer. 2000. St.
John’s wort induces hepatic drug metabolism through activation
of the pregnane X receptor. Proceedings of the National
Academy of Sciences 97: 7500–7502.
Muhammad, I., R. Afza, and S. Yousaf. 2006. Ethnopharmacological
survey of plants used for the treatment of stomach, diabetes, and
ophthalmic diseases in Sudhan Gali, Kashmir, Pakistan. Acta
Botanica Yunnanica 28: 535–542.
Narendhirakannan, R., S. Subramanian, and M. Kandaswamy. 2006.
Biochemical evaluation of antidiabetogenic properties of some
commonly used Indian plants on streptozotocin-induced diabetes
in experimental rats. Clinical and Experimental Pharmacology
and Physiology 33: 1150–1157.
National Institutes of Health Office of Dietary Supplements. 2013.
Botanical dietary supplements: Background information.
Retrieved, from http://ods.od.nih.gov/factsheets/botanicalback
ground.asp.
Nebert, D.W., and D.W. Russell. 2002. Clinical importance of the
cytochromes P450. The Lancet 360: 1155–1162.
Nirmala, A., I. Eliza, M. Rajalakshmi, E. Priya, and P. Daisy. 2008.
Effect of hexane extract of Cassia fstula barks on blood glucose
and lipid profile in streptozotocin diabetic rats. International
Journal of Pharmacology 4: 292–296.
Nivitabishekam, S.N., M. Asad, and V.S. Prasad. 2009. Pharmaco-
dynamic interaction of Momordica charantia with rosiglitazone
in rats. Chemico-Biological Interactions 177: 247–253.
Norlin, M., and K. Wikvall. 2007. Enzymes in the conversion of
cholesterol into bile acids. Current Molecular Medicine 7:
199–218.
Nowack, R. 2008. Cytochrome P450 enzyme, and transport protein
mediated herb–drug interactions in renal transplant patients:
Grapefruit juice, St. John’s wort—and beyond! Nephrology 13:
337–347.
Obach, R.S. 2000. Inhibition of human cytochrome P450 enzymes by
constituents of St. John’s wort, an herbal preparation used in the
treatment of depression. Journal of Pharmacology and Exper-
imental Therapeutics 294: 88–95.
Ono, S., T. Hatanaka, H. Hotta, T. Satoh, F. Gonzalez, and M.
Tsutsui. 1996. Specificity of substrate and inhibitor probes for
cytochrome P450s: evaluation of in vitro metabolism using
123
S. Rehman et al.
cDNA-expressed human P450s and human liver microsomes.
Xenobiotica 26: 681–693.
Ooi, J.P., M. Kuroyanagi, S.F. Sulaiman, T.S.T. Muhammad, and
M.L. Tan. 2011. Andrographolide and 14-deoxy-11, 12-didehy-
droandrographolide inhibit cytochrome P450s in HepG2 hepa-
toma cells. Life Sciences 88: 447–454.
Pan, Y., B.A. Abd-Rashid, Z. Ismail, R. Ismail, J.W. Mak, P.C. Pook,
H.M. Er, and C.E. Ong. 2011a. In vitro modulatory effects of
Andrographis paniculata, Centella asiatica and Orthosiphon
stamineus on cytochrome P450 2C19 (CYP2C19). Journal of
Ethnopharmacology 133: 881–887.
Pan, Y., B.A. Abd-Rashid, Z. Ismail, R. Ismail, J.W. Mak, P.C. Pook,
H.M. Er, and C.E. Ong. 2011b. In vitro determination of the
effect of Andrographis paniculata extracts and andrographolide
on human hepatic cytochrome P450 activities. Journal of
Natural Medicines 65: 440–447.
Persiani, S., L. Canciani, P. Larger, R. Rotini, G. Trisolino, D.
Antonioli, and L. Rovati. 2009. In vitro study of the inhibition and
induction of human cytochromes P450 by crystalline glucosamine
sulfate. Drug Metabolism and Drug Interactions 24: 195–210.
Qiu, F., G. Wang, R. Zhang, J. Sun, J. Jiang, and Y. Ma. 2010. Effect
of danshen extract on the activity of CYP3A4 in healthy
volunteers. British Journal of Clinical Pharmacology 69:
656–662.
Qiu, F., R. Zhang, J. Sun, A. Jiye, H. Hao, Y. Peng, H. Ai, and G.
Wang. 2008. Inhibitory effects of seven components of danshen
extract on catalytic activity of cytochrome P450 enzyme in
human liver microsomes. Drug Metabolism and Disposition 36:
1308–1314.
Rahbar, A., R. Shakerhosseini, N. Saadat, F. Taleban, A. Pordal, and
B. Gollestan. 2005. Effect of L-carnitine on plasma glycemic and
lipidemic profile in patients with type II diabetes mellitus.
European Journal of Clinical Nutrition 59: 592–596.
Raman, A., and C. Lau. 1996. Anti-diabetic properties and phyto-
chemistry of Momordica charantia L. (Cucurbitaceae). Phyto-
medicine 2: 349–362.
Ratnasooriya, W.D., J.R. Jayakody, and H.D. Hettiarachchi. 2004.
Cassia fistula and hypoglycaemia. Australian Journal of Medical
Herbalism 16: 8.
Raza, H., I. Ahmed, A. John, and A.K. Sharma. 2000. Modulation of
xenobiotic metabolism and oxidative stress in chronic strepto-
zotocin-induced diabetic rats fed with Momordica charantia fruit
extract. Journal of Biochemical and Molecular Toxicology 14:
131–139.
Raza, H., I. Ahmed, M.S. Lakhani, A.K. Sharma, D. Pallot, and W.
Montague. 1996. Effect of bitter melon (Momordica Charantia)
fruit juice on the hepatic cytochrome P450-dependent monoox-
ygenases and glutathione S-transferases in streptozotocin-
induced diabetic rats. Biochemical Pharmacology 52:
1639–1642.
Reyes, B., N. Bautista, N. Tanquilut, R. Anunciado, A. Leung, G.
Sanchez, R. Magtoto, P. Castronuevo, H. Tsukamura, and K.I.
Maeda. 2006. Anti-diabetic potentials of Momordica charantia
and Andrographis paniculata and their effects on estrous
cyclicity of alloxan-induced diabetic rats. Journal of Ethnophar-
macology 105: 196–200.
Richard, A.J., Z.J. Amini, D.M. Ribnicky, and J.M. Stephens. 2012.
St. John’s wort inhibits insulin signaling in murine and human
adipocytes. Biochimica et Biophysica Acta (BBA) 1822:
557–563.
Rowin, J., and S.L. Lewis. 1996. Spontaneous bilateral subdural
hematomas associated with chronic Ginkgo biloba ingestion.
Neurology 46: 1775–1776.
Samson, R. 1982. Effects of dietary garlic and temporal drift on
platelet aggregation. Atherosclerosis 44: 119–120.
Interactions between herbs and antidiabetics
Scott, G.N., and G.W. Elmer. 2002. Update on natural product–drug
interactions. American Journal of Health-system Pharmacy 59:
339–347.
Scroggie, D.A., A. Albright, and M.D. Harris. 2003. The effect of
glucosamine-chondroitin supplementation on glycosylated
hemoglobin levels in patients with type 2 diabetes mellitus: A
placebo-controlled, double-blinded, randomized clinical trial.
Archives of Internal Medicine 163: 1587.
Sen, S., M.A. Querques, and S. Chakrabarti. 2013. North American
Ginseng (Panax quinquefolius) prevents hyperglycemia and
associated pancreatic abnormalities in diabetes. Journal of
Medicinal Food 16: 587–592.
Singh, K.N., and U.R. Bharadwaj. 1975. Hypoglycaemic activity of
Albizzia stipulata, Albizzia moluccana and Cassia fistula legu-
minous seed diets on normal young rats. Indian Journal of
Pharmacology 7: 47.
Skalli, S., A. Zaid, and R. Soulaymani. 2007. Drug interactions with
herbal medicines. Therapeutic Drug Monitoring 29: 679–686.
Smith, M., K. Lin, and Y. Zheng. 2001. An open trial of nifedipine-
herb interactions: Nufedipine with St. John’s wort, Ginseng or
Ginko biloba. Clinical Pharmacology & Therapeutics, P86–P86.
St. Louis: Mosby, Inc.
Solimene, U., A. Alkofahi, C. Allemann, M. Amigoni, R. Aspan,
S. Azimova, B.C. Bloodworth, G. Caccialanza, A. Caizzi,
and M. Cheraghali. 2007. WHO guidelines for assessing
quality of herbal medicines with reference to contaminants
and residues.
Srivastava, Y., H. Venkatakrishna-Bhatt, Y. Verma, K. Venkaiah, and
B. Raval. 1993. Antidiabetic and adaptogenic properties of
Momordica charantia extract: An experimental and clinical
evaluation. Phytotherapy Research 7: 285–289.
Sugiyama, T., Y. Kubota, K. Shinozuka, S. Yamada, K. Yamada, and
K. Umegaki. 2004a. Induction and recovery of hepatic drug
metabolizing enzymes in rats treated with Ginkgo biloba extract.
Food and Chemical Toxicology 42: 953–957.
Sugiyama, T., J.I. Nagata, A. Yamagishi, K. Endoh, M. Saito, K.
Yamada, S. Yamada, and K. Umegaki. 2006. Selective protec-
tion of curcumin against carbon tetrachloride-induced inactiva-
tion of hepatic cytochrome P450 isozymes in rats. Life Sciences
78: 2188–2193.
Sugiyama, T., K. Shinozuka, A. Sano, S. Yamada, K. Endoh, K.
Yamada, and K. Umegaki. 2004b. Effects of various Ginkgo
biloba extracts and proanthocyanidin on hepatic cytochrome
P450 activity in rats. Journal of the Food Hygienic Society of
Japan 45: 295.
Sun, C., Y. Chen, X. Li, G. Tai, Y. Fan, and Y. Zhou. 2014. Anti-
hyperglycemic and anti-oxidative activities of ginseng polysac-
charides in STZ-induced diabetic mice. Food and Function 5:
845–848.
Sun, H., Z. Zuo, O. Yin, B. Tomlinson, and M. Chow. 2002. A ‘‘high-
throughput’’ cocktail method for screening the effect of herbal
product on liver isozyme activities: Experience with Ginkgo
biloba. Clinical Pharmacology & Therapeutics 71: P100–P100.
Swanston, S.K., C. Day, C. Bailey, and P. Flatt. 1990. Traditional
plant treatments for diabetes. Studies in normal and streptozo-
tocin diabetic mice. Diabetologia 33: 462–464.
Tachjian, A., V. Maria, and A. Jahangir. 2010. Use of herbal products
and potential interactions in patients with cardiovascular
diseases. Journal of the American College of Cardiology 55:
515–525.
Tarirai, C., A.M. Viljoen, and J.H. Hamman. 2010. Herb–drug
pharmacokinetic interactions reviewed. Expert Opinion on Drug
Metabolism and Toxicology 6: 1515–1538.
Tiwari, J.K., L.R. Dangwal, C.S. Rana, P. Tiwari, and R. Ballabha.
2010. Indigenous uses of plant species in Nanda Devi Biosphere
Reserve, Uttarakhand, India. Report and Opinion 2: 58–61.
Tongia, A., S.K. Tongia, and M. Dave. 2004. Phytochemical
determination and extraction of Momordica charantia fruit and
its hypoglycemic potentiation of oral hypoglycemic drugs in
diabetes mellitus (NIDDM). Indian Journal of Physiology and
Pharmacology 48: 241–244.
Tseng-Crank, J., S.G. Do, B. Corneliusen, C. Hertel, J. Homan, M.
Yimam, J. Zhao, and Q. Jia. 2013. UP780, A chromone-enriched
aloe composition, enhances adipose insulin receptor signaling
and decreases liver lipid biosynthesis. Open Journal of Genetics
3: 9.
Uchida, S., H. Yamada, X.D. Li, S. Maruyama, Y. Ohmori, T. Oki, H.
Watanabe, K. Umegaki, K. Ohashi, and S. Yamada. 2006. Effects
of Ginkgo biloba extract on pharmacokinetics and pharmacody-
namics of tolbutamide and midazolam in healthy volunteers. The
Journal of Clinical Pharmacology 46: 1290–1298.
Unger, M., and A. Frank. 2004. Simultaneous determination of the
inhibitory potency of herbal extracts on the activity of six major
cytochrome P450 enzymes using liquid chromatography/mass
spectrometry and automated online extraction. Rapid Communi-
cations in Mass Spectrometry 18: 2273–2281.
Vale, S. 1998. Subarachnoid haemorrhage associated with Ginkgo
biloba. The Lancet 352: 36.
Van Dam, R. 2006. Coffee and type 2 diabetes: From beans to beta-
cells. Nutrition, Metabolism and Cardiovascular Diseases 16:
69–77.
Van den Bout-Van Den Beukel, C.J., J. Carolien, O.J. Hamza, M.J.
Moshi, M.I. Matee, F. Mikx, D.M. Burger, P.P. Koopmans, P.E.
Verweij, and W.G. Schoonen. 2008. Evaluation of cytotoxic,
genotoxic and CYP450 enzymatic competition effects of Tan-
zanian plant extracts traditionally used for treatment of fungal
infections. Basic and Clinical Pharmacology and Toxicology
102: 515–526.
Van Dam, R.M., W.J. Pasman, and P. Verhoef. 2004. Effects of
coffee consumption on fasting blood glucose and insulin
concentrations randomized controlled trials in healthy volun-
teers. Diabetes Care 27: 2990–2992.
Virdi, J., S. Sivakami, S. Shahani, A. Suthar, M. Banavalikar, and M.
Biyani. 2003. Antihyperglycemic effects of three extracts from
Momordica charantia. Journal of Ethnopharmacology 88:
107–111.
Vuksan, V., J.L. Sievenpiper, V.Y. Koo, T. Francis, U. Beljan-
Zdravkovic, Z. Xu, and E. Vidgen. 2000a. American ginseng
(Panax quinquefolius L.) reduces postprandial glycemia in
nondiabetic subjects and subjects with type 2 diabetes mellitus.
Archives of Internal Medicine 160: 1009.
Vuksan, V., M.P. Stavro, J.L. Sievenpiper, U. Beljan-Zdravkovic,
L.A. Leiter, R.G. Josse, and Z. Xu. 2000b. Similar postprandial
glycemic reductions with escalation of dose and administration
time of American ginseng in type 2 diabetes. Diabetes Care 23:
1221–1226.
Vuksan, V., M.P. Stavro, J.L. Sievenpiper, V.Y. Koo, E. Wong, U.
Beljan-Zdravkovic, T. Francis, A.L. Jenkins, L.A. Leiter, and
R.G. Josse. 2000c. American ginseng improves glycemia in
individuals with normal glucose tolerance: Effect of dose and
time escalation. Journal of the American College of Nutrition 19:
738–744.
Vuksan, V., M.K. Sung, J.L. Sievenpiper, P.M. Stavro, A.L. Jenkins,
M. Di Buono, K.S. Lee, L.A. Leiter, K.Y. Nam, and J.T.
Arnason. 2008. Korean red ginseng (Panax ginseng) improves
glucose and insulin regulation in well-controlled, type 2
diabetes: Results of a randomized, double-blind, placebo-
controlled study of efficacy and safety. Nutrition, Metabolism
and Cardiovascular Diseases 18: 46–56.
Walker, B.R., N.R. Colledge, S.H. Ralston, and I. Penman. 2013.
Davidson’s principles and practice of medicine. New York:
Elsevier.
123

Walker, P.S., and J.A. Donovan. 1999. Herbal remedies: Natural
caveats. International Journal of Dermatology 38: 746–748.
Wang, J.F., and K.C. Chou. 2010. Molecular modeling of cytochrome
P450 and drug metabolism. Current Drug Metabolism 11:
342–346.
Wang, Z., J.C. Gorski, M.A. Hamman, S.M. Huang, L.J. Lesko, and
S.D. Hall. 2001. The effects of St. John’s wort (Hypericum
perforatum) on human cytochrome P450 activity. Clinical
Pharmacology and Therapeutics 70: 317–326.
Welihinda, J., E. Karunanayake, M. Sheriff, and K. Jayasinghe. 1986.
Effect of Momordica charantia on the glucose tolerance in
maturity onset diabetes. Journal of Ethnopharmacology 17:
277–282.
Whiting, D.R., L. Guariguata, C. Weil, and J. Shaw. 2011. IDF
diabetes atlas: Global estimates of the prevalence of diabetes for
2011 and 2030. Diabetes Research and Clinical Practice 94:
311–321.
Whitten, D., S. Myers, J. Hawrelak, and H. Wohlmuth. 2006. The
effect of St. John’s wort extracts on CYP3A: A systematic
review of prospective clinical trials. British Journal of Clinical
Pharmacology 62: 512–526.
Williamson, E.M., S. Driver, K. Baxter, and C.R. Lee. 2013.
Stockley’s herbal medicines interactions. London: Pharmaceuti-
cal Press.
Xiong, Y., L. Shen, K.J. Liu, P. Tso, Y. Xiong, G. Wang, S.C. Woods,
and M. Liu. 2010. Antiobesity and antihyperglycemic effects of
ginsenoside Rb1 in rats. Diabetes 59: 2505–2512.
Xu, H., K. Williams, W. Liauw, M. Murray, R. Day, and A.
Mclachlan. 2008. Effects of St. John’s wort and CYP2C9
genotype on the pharmacokinetics and pharmacodynamics of
gliclazide. British Journal of Pharmacology 153: 1579–1586.
Yagi, A. 2014. Possible efficacy of aloe vera gel metabolites in long-
term ingestion to insulin sensitivity. Journal of Gastroenterology
and Hepatology Research 3: 996-1005.
Yale, S.H., and I. Glurich. 2005. Analysis of the inhibitory potential
of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on
the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.
Journal of Alternative and Complementary Medicine 11:
433–439.
Yeleswaram, K., N. Vachharajani, and K. Santone. 1999. Involve-
ment of cytochrome P-450 isozymes in melatonin metabolism
and clinical implications. Journal of Pineal Research 26:
190–191.
Yimam, M., J. Zhao, B. Corneliusen, M. Pantier, L. Brownell, and Q.
Jia. 2014. Blood glucose lowering activity of aloe based
composition, UP780, in alloxan induced insulin dependent mice
diabetes model. Diabetology and Metabolic Syndrome 6: 61.
123
S. Rehman et al.
Yimam, M., J. Zhao, B. Corneliusen, M. Pantier, L.A. Brownell, and
Q. Jia. 2013. UP780, a chromone-enriched aloe composition
improves insulin sensitivity. Metabolic Syndrome and Related
Disorders 11: 267–275.
Yin, O.Q., B. Tomlinson, M.M. Waye, A.H. Chow, and M.S. Chow.
2004. Pharmacogenetics and herb–drug interactions: Experience
with Ginkgo biloba and omeprazole. Pharmacogenetics and
Genomics 14: 841–850.
Yongchaiyudha, S., V. Rungpitarangsi, N. Bunyapraphatsara, and O.
Chokechaijaroenporn. 1996. Antidiabetic activity of Aloe vera L.
juice. I. Clinical trial in new cases of diabetes mellitus.
Phytomedicine 3: 241–243.
Yoo, K.M., C. Lee, Y.M. Lo, and B. Moon. 2012. The hypoglycemic
effects of American red ginseng (Panax quinquefolius L.) on a
diabetic mouse model. Journal of Food Science 77: H147–H152.
Yoo, H.H., M.W. Lee, Y.C. Kim, C.H. Yun, and D.H. Kim. 2007.
Mechanism-based inactivation of cytochrome P450 2A6 by
decursinol angelate isolated from Angelica gigas. Drug Metab-
olism and Disposition 35: 1759–1765.
Yoo, H.H., S.H. Lee, C. Jin, and D.H. Kim. 2008. Mechanism-based
inactivation of cytochrome P450 3A4 by methylenedioxyphenyl
lignans from Acanthopanax chiisanensis. Planta Medica 74: 808–813.
Yu, B.C., W.C. Chen, and J.T. Cheng. 2003a. Antihyperglycemic
effect of andrographolide in streptozotocin-induced diabetic rats.
Planta Medica 69: 1075–1079.
Yu, C., Y.G. Shin, J.W. Kosmeder, J.M. Pezzuto, and R.B. van
Breemen. 2003b. Liquid chromatography/tandem mass spectro-
metric determination of inhibition of human cytochrome P450
isozymes by resveratrol and resveratrol-3-sulfate. Rapid Com-
munications in Mass Spectrometry 17: 307–313.
Zhang, X.F., and B.K. Tan. 2000. Antihyperglycemic and anti-
oxidant properties of Andrographis paniculata in normal and
diabetic rats. Clinical and Experimental Pharmacology and
Physiology 27: 358–363.
Zhao, R., Q. Li, and B. Xiao. 2005. Effect of Lycium barbarum
polysaccharide on the improvement of insulin resistance in
NIDDM rats. Yakugaku Zasshi 125: 981–988.
Zhong, Z., C. Wang, W. Wang, L. Shen, and Z. Chen. 2014. Major
hypoglycemic ingredients of panax notoginseng saponins for
treating diabetes. Journal of Sichuan University (Medical
Science Edition) 45: 235–239.
Zhou, S.F., and X. Lai. 2008. An Update on Clinical Drug
Interactions with the Herbal Antidepressant St. John’s wort.
Current Drug Metabolism 9: 394–409.
Zou, L., M. Harkey, and G. Henderson. 2002. Effects of herbal
components on cDNA-expressed cytochrome P450 enzyme
catalytic activity. Life Sciences 71: 1579–1589.