Alimentary Pharmacology & Therapeutics

Review article: 5-aminosalicylate formulations for the treatment

of ulcerative colitis methods of comparing release rates and
delivery of 5-aminosalicylate to the colonic mucosa
G. R. LICHTENSTEIN* & M. A. KAMM

*Division of Gastroenterology,
University of Pennsylvania School of
Medicine, Philadelphia, PA, USA;
Department of Gastroenterology,
St. Marks Hospital, London, UK
Correspondence to:
Dr G. R. Lichtenstein, Department of
Medicine, Division of
Gastroenterology, Hospital of the
University of Pennsylvania, 3rd Floor
Ravdin Building, 3400 Spruce Street,
Philadelphia, PA 19104-4283, USA.
E-mail:
gary.lichtenstein@uphs.upenn.edu

Publication data
Submitted 11 March 2008
First decision 1 April 2008
Resubmitted 30 May 2008
Accepted 31 May 2008
Epub Accepted Article 3 June 2008

SUMMARY
Background
Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to
maximize 5-ASA release in the colon where it acts topically on the
colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract.
Aims
To review methods for assessing 5-ASA release and colonic distribution
from oral formulations, and the potential use of this information for
guiding clinical decisions.
Methods
PubMed and recent conference abstracts were searched for articles
describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies.
Results
In-vitro GI models, although unable to simulate more complex aspects
of GI physiology, can provide useful data on 5-ASA release kinetics
and bioaccessibility. Gamma-scintigraphy is useful for investigating GI
disintegration of different formulations, but may not accurately reflect
5-ASA distribution. Plasma pharmacokinetic studies provide data on
systemic exposure, but not on colonic distribution or mucosal uptake.
Mucosal biopsies provide direct evidence of colonic distribution and
may predict clinical efficacy, but must be interpreted cautiously because
of considerable inter-subject variability and other confounding factors.
Conclusion
While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in
UC patients remain the best guide for dosing and treatment regimen
decisions.
Aliment Pharmacol Ther 28, 663673

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664 G . R . L I C H T E N S T E I N and M . A . K A M M

INTRODUCTION
Ulcerative colitis (UC) is a chronic, idiopathic inflammatory disorder affecting the colon and rectum, characterized by an unpredictable course of relapse and
remission.1 At first presentation of the disease, approximately 40% of adult patients have UC that is limited to
the rectum, known as proctitis.2 Left-sided or distal
colitis, defined as UC extending proximally in the colon
but not beyond the splenic flexure (approximately
60 cm from the anal verge), occurs in approximately
40% of adult patients presenting with UC. Less than
20% of adult patients at presentation have extensive
UC, which extends proximally to the splenic flexure.2
The cardinal symptom of UC is diarrhoea containing
blood and mucus. However, many patients with UC
also develop other symptoms and abnormalities
including abdominal pain, tenesmus, anaemia and
weight loss.1, 3, 4 Less common symptoms can include
arthritis arthralgias, cutaneous conditions, renal disorders, osteoporosis, and inflammation of the eye, liver
and biliary system.3, 5
The recommended first-line therapy for the treatment of active symptoms, induction of remission and
maintenance of remission in patients with mild-tomoderate UC is the anti-inflammatory agent 5-aminosalicylic acid (5-ASA; mesalazine; Figure 1).1, 6 A
number of potential targets for 5-ASA action have
been proposed; among these is the peroxisome proliferator-activated receptor-c (PPAR-c), which is known
to be involved in UC inflammation.7 Indeed, 5-ASA
can act as a synthetic agonist of PPAR-c.8 However,
additional mechanisms of action, independent of
PPAR-c activation, have also been proposed. These
include the inhibition of: prostaglandin synthesis
(via inhibition of cyclo-oxygenase); chemotactic
leukotriene synthesis (via inhibition of lipoxygenase);9
interleukin-1 (IL-1) synthesis;10, 11 and nuclear factorkappa B activation by tumour necrosis factor alpha12

and IL-1.13 5-ASA may also act as a biological antioxidant by scavenging oxygen free radicals.14
As 5-ASA is believed to exert a direct effect on the
colonic mucosa through a variety of anti-inflammatory mechanisms,15 direct application of this agent to
the colonic mucosa is required. There are a number of
strategies for achieving this delivery to the target tissue. Rectal administration of gels, foams and enemas
containing 5-ASA is effective for administering the
active drug directly to the rectum, sigmoid or left
colon. Indeed, recent studies in patients with extensive
UC have shown that combination of both oral and rectal therapies may maximize 5-ASA concentration
throughout the colon and is superior to oral therapy
alone.16 However, patients often dislike rectal formulations because of difficulty with this mode of administration and problems with discomfort, retention and
leakage.1719 In contrast, the variety of currently available oral 5-ASA formulations are more acceptable to
patients.
Oral administration of 5-ASA presents a different
challenge as the majority of oral 5-ASA, when taken
in an unformulated fashion, is rapidly absorbed in the
small intestine, leaving little or no 5-ASA to treat the
colon (Figure 2). Sulfasalazine was the first 5-ASA to
be used for the treatment and maintenance of symptoms of UC. The azo-bonded sulfapyridine molecule
protects the active drug until bacterial azoreductase

Oral 5-ASA

Unformulated
absorption

Small intestine

N-Ac-5-ASA

Blood

Optimal
delivery

Large intestine
Kidney

Excretion

COOH

Liver
5-ASA

5-ASA

Faeces N-Ac-5-ASA

Urine

5-ASA
N-Ac-5-ASA

OH

H2N

Figure 1. The chemical structure of 5-aminosalicylic acid

(5-amino-2-hydroxybenzoic acid).

Figure 2. Proposed metabolic pathway of 5-ASA after

oral administration. The shaded area (large intestine) indicates the site of topical action. Unformulated 5-ASA is
absorbed rapidly from the small intestine, and many current formulations are designed to delay release of 5-ASA
until the terminal ileum or proximal colon. 5-ASA,
5-aminosalicylic acid; N-AC-5-ASA, N-acetyl-5-ASA.
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cleavage in the colon. However, the sulfasalazine molecule is associated with allergic reactions and a number of dose-dependent adverse effects.20 As a result,
formulations based on the active moiety, 5-ASA, have
been developed.1, 3, 21 Two main methods have been
employed by manufacturers of 5-ASA-based UC treatments to prevent upper-gastrointestinal (GI) 5-ASA
release.15, 17 The first is to link 5-ASA (as with sulfasalazine, via a di-azo bond) to another compound to
form a non-absorbable prodrug. This molecule can
then be cleaved in the colon by the bacterial enzyme
azoreductase. Agents that utilize this strategy are
balsalazide and olsalazine (in which the 5-ASA molecule is coupled to a benzoic acid derivative or another
5-ASA molecule). The second strategy is to coat the
formulation in a gastro-resistant coating that prevents
5-ASA release until luminal conditions approach pH 7
(normally in the terminal ileum). This allows a bolus
of 5-ASA to be released in the terminal ileum and the
proximal colon. Such formulations include Asacol
delayed-release mesalazine tablets (Procter & Gamble
Pharmaceuticals, Cincinnati, OH, USA); Salofalk tablets
(Axcan Pharma, Mont St Hilaire, QC, Canada) and
Salofalk Granustix (Axcan Pharma).
Historically, there have been two drawbacks common to these oral 5-ASA-based UC therapies. Firstly,
azo-bonded and delayed (bolus)-release formulations
may not deliver therapeutically effective doses of 5ASA to the left side of the colon (a site affected in all
patients with UC). Indeed, clinical studies have shown
that mucosal 5-ASA concentrations using azo-bonded
or bolus-release formulations are typically highest in
the right-sided colon, whereas in the rectum the concentration of 5-ASA is much lower.22, 23 Secondly, it
has thus far been necessary to dose these formulations
multiple times daily. This has been considered essential to ensure that therapeutically effective 5-ASA
doses are maintained in the colon, and indeed, formulations dosed in this way have been shown to be efficacious for the treatment of UC in clinical studies.1, 6
However, patient compliance with these dosing schedules has been demonstrated to be poor in clinical practice, leading to reduced drug efficacy and thus poorer
disease control (i.e. an increased number of UC
flares).2427
Recently, new technologies have been used to
address the problem of bolus release of 5-ASA. MMX
Multi Matrix System technology (Shire Pharmaceuticals Inc., Wayne, PA, USA), utilizes lipophilic and
hydrophilic excipients to allow prolonged release of
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5-ASA throughout the colon, following degradation of

a gastro-resistant coating. This delivery system allows
once-daily administration of high-concentration tablets (1.2 g 5-ASA per tablet).28, 29 Another formulation
that avoids bolus release is Pentasa (Shire Pharmaceuticals Inc.; trademark licensed from Ferring A S,
Copenhagen, Denmark) which comprises 5-ASA containing microspheres enclosed within a moisture-sensitive, ethylcellulose, semi-permeable membrane. This
allows pH-independent release of the active drug.
Unlike other formulations, Pentasa starts releasing 5ASA in the duodenum and continues throughout the
entire GI tract.
Micropellet release systems are becoming more
widespread. Provided as individual sachets containing
a single dose, these formulations utilize granules to
effect a delayed and sustained release of 5-ASA with
similar delivery properties and systemic exposure to
tablets.30, 31 Salofalk 500 mg and 1 g (Axcan Pharma
and Falk Pharma, Freiburg, Germany) and Pentasa 1 g
(Ferring A S) are currently available in some European
markets. Phase III trials are continuing in the US and
a 1.5 g, once daily encapsulated mesalazine micropellet formulation (Salofalk Granustix) is also in clinical
development (Salix Pharmaceuticals Inc., Morrisville,
NC, USA).
Although randomized clinical trials have demonstrated that various formulations of 5-ASA are effective in either treating symptoms or inducing remission
in UC,1, 6, 28, 29 it has been difficult to elucidate how
each formulation or delivery system releases 5-ASA in
the GI tract. This is further complicated by the variability in transit times and pH conditions that exist in
UC patients, which can have a large impact on how 5ASA is released from formulations and taken up by
the colonic mucosa.32 While data exist pertaining to
the predicted release mechanism of the various 5-ASA
formulations, these data are not precise, which is in
part because of limitations in the techniques available
to perform these measures. Nevertheless, over the past
20 years, numerous studies have been performed that
have added to our understanding of the release of 5ASA from different formulations using a variety of
different methods. These include: traditional pharmacokinetic (PK) investigations;33 simulated GI tract systems;34, 35 insertion of intestinal multilumen tubes for
aspiration and marker perfusion;36 in-vitro dissolution
tests;37, 38 gamma scintigraphy30, 31, 3944 and tissue
biopsy.22, 45 This review will compare the major techniques that are currently used in the study of 5-ASA

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release and will discuss what can be concluded from

each technique in terms of formulation release characteristics, and 5-ASA bioaccessibility and efficacy.

Simulated GI models
Simulated GI models are a relatively recent development and are used to study the fate of ingested products in a dynamic bioenvironment that closely mimics
the physiological conditions in the lumen of the
human adult GI tract.46, 47 These model systems have
frequently been used for investigating the bioaccessibility and site of action of nutritional supplements.4850
While such systems cannot assess efficacy, they
do provide a standardized environment in which to
investigate the dissolution characteristics of 5-ASA
formulations in a way that is not possible using other
techniques.
A simulated GI model [the GI simulated system
(GISS)] has been used to assess the release characteristics of several commercially available 5-ASA products
for the treatment of UC.34 This system consists of four
vessels, which are used to simulate the stomach, jejunum, ileum and proximal colon, respectively.
Although transit time, pH, osmolarity and agitation
can be varied and controlled with the GISS, it lacks
the simulation of peristalsis and the removal of digestion disintegration products. Despite these limitations,
however, some interesting results have been observed,
which provide information regarding the release characteristics of delayed-release 5-ASA formulations. All
three of the delayed-release products assessed (Asacol
tablet, Salofalk tablet, and Salofalk Granustix in
sachet) began releasing 5-ASA in the proximal and
mid parts of the simulated small intestine. The two
tablet formulations released most of their 5-ASA prior
to entry to the simulated colon, but by the end of the
experiment had cumulatively released almost the
entire administered dose of 5-ASA. In contrast, Salofalk Granustix had a much slower release profile, with
5-ASA being steadily released in the simulated
colon.34 However, 5-ASA was released so slowly from
the sachet formulation that less than half of the total
dose was released by the end of the experiment.34
Therefore, it is a distinct possibility that while a
patient may consume apparently similar doses of
active drug, from various formulations, the actual concentration of 5-ASA delivered and where it is released
may differ substantially, thus potentially affecting
clinical efficacy.

Another GI model, the TNO GastroIntestinal

Model (TIM system; TNO Quality of Life, Zeist, The
Netherlands), is available for studying drug release in
a simulated GI tract.35 This system consists of two
computer-controlled, multicompartmental systems that
simulate peristaltic movements and introduce gastric biliary pancreatic secretions in a controlled
environment. The first system (TIM-1) simulates the
stomach and small intestine and the second (TIM-2)
simulates the colon.35 Recently, release kinetics of
5-ASA from MMX mesalazine tablets (Mezavant;
Lialda) were assessed using the TIM system. The
release kinetics of 5-ASA were investigated under
standardized fed and fasted conditions with automated
sampling via dialysis at various sections of the system.
Less than 1% of the 5-ASA was released from the
tablet in the simulated stomach and small intestine
(prior to introduction into the simulated colon).
Under fasted conditions, 78% of the 5-ASA was
released into the simulated colon and under fed
conditions, 68.5% was released. Notably, substantial
quantities of 5-ASA were released during the 818-h
sampling period [49.6 mg h (fasted) and 40.7 mg h
(fed)]. Importantly, and in contrast to other techniques
such as plasma PK analysis, this particular system
allows a spatial-time analysis to determine where in
the simulated colon 5-ASA was released. Indeed, the
authors reported that under both simulated fasted- and
fed-state conditions, cumulative 5-ASA recovery in
the colon dialysate was sigmoidal in nature. These
data support the notion that MMX technology prolongs release of 5-ASA from MMX mesalazine in a
way that may allow greater distribution of 5-ASA
throughout the colon.
Ultimately, while the usefulness of in-vitro systems
is limited by the fact that they are not able to completely replicate human gut physiology (including the
complex immunological and inflammatory factors that
are present in patients with UC), and provide no information on the clinical effectiveness of 5-ASA therapies, the results from these two in-vitro studies clearly
demonstrate that simulated GI models have a role to
play in providing information regarding 5-ASA release
profiles. Indeed, such model systems allow reproducible results to be obtained rapidly and in a non-invasive fashion. Perhaps the greatest advantage of
in-vitro systems over the other methods of assessing
release of 5-ASA from oral UC therapies is that they
allow different formulations to be compared in a standardized environment.
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Gamma-scintigraphy
Gamma-scintigraphy was originally developed as a
technique for detecting gamma-ray emitting molecules
localized in specific structures and organs of the body.
The incorporation of gamma-emitters into drug formulations allows gamma-scintigraphy to be used to visualize the distribution or accumulation of drug within the
body.40, 41, 5154 Gamma-scintigraphy requires that a
drug formulation be labelled with a gamma-radiationemitting tracer. This can be achieved either by directly
incorporating a gamma-emitting compound into the
dosage form, or by neutron activation of a formulation
containing a nonradioactive tracer. Because gammaemitters are rare amongst the constituent elements of
the majority of drugs (e.g. hydrogen, carbon, nitrogen,
oxygen, phosphorous and sulphur), alternative strategies employing other elements are required for gammascintigraphy. For the evaluation of the transit and
disintegration of complex formulations, such as entericcoated tablets or pellets, labelling can be performed by
the addition of a nonradioactive tracer (e.g. samarium152 oxide) that is not absorbed from the GI tract.
Samarium-152 oxide can then be converted into a
gamma-emitter (samarium-153) by neutron activation
of the formulated product.31, 51, 55, 56 This approach
enables the fate of the tracer to be followed once
released from the formulation. However, a limitation of
the technique is that the drug and tracer are separate
and their disposition after release may be different.
A number of studies have utilized gamma-scintigraphy to assess the release characteristics of oral 5-ASA
formulations.30, 39, 40, 42, 53, 57, 58 In these studies,
gamma-scintigraphy was used to visualize intact gastro-resistant tablets travelling through the upper-GI
tract and their subsequent dissolution, together with
progression of the radioactive tracer molecule through
the colon at more advanced timepoints.30, 39, 40, 57 However, while scintigraphic images gave a partial impression of release, they could not quantify the amount of
5-ASA released, which might have occurred at a different rate from that of the tracer. Ultimately, while being
a useful tool, gamma-scintigraphy provides no accurate
information on the subsequent distribution and fate of
5-ASA once it is released from the formulation.

Plasma pharmacokinetics
Often, for a drug with a site of action in rapid equilibrium with plasma, estimating therapeutic effects is
2008 The Authors, Aliment Pharmacol Ther 28, 663673
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helped by an understanding of the drugs distribution

within the body (PK). It may also be necessary to
understand how the effects of the drug at the site of
action [pharmacodynamics (PD)] relate to their concentration in the plasma. For some drugs, plasma PK
and PD can be used in clinical practice to guide
manipulation of dose and dosage regimens to optimize
therapies within tolerable limits. However, as 5-ASA
acts topically in the treatment of UC, systemic exposure to 5-ASA is not necessarily related to therapeutic
efficacy. Moreover, because only low levels of 5-ASA
are released into the plasma via the colonic mucosa, it
is difficult to relate mucosal concentrations of 5-ASA
or how 5-ASA is distributed along the length of the
colon to the plasma concentration.
Poor uptake of 5-ASA from the colonic mucosa into
the bloodstream is caused partly by the hydrophilic
nature of 5-ASA, which means that only a very small
proportion of the 5-ASA in the colon will diffuse into
the plasma through lipid membranes.59 Furthermore,
paracellular absorption is reduced at the tight junctions of the colonic mucosa, further reducing the
extent of systemic absorption, particularly for
delayed-release and azo-bonded formulations compared with formulations that release more 5-ASA into
the small intestine. Also, 5-ASA and its metabolite [Nacetyl-5-ASA (N-Ac-5-ASA)] are secreted back into
the colonic lumen following uptake into the colonic
mucosa,60 reducing further the amount of 5-ASA that
will progress to the plasma. These observations are
supported by clinical data, which show that serum
concentrations of 5-ASA after colonic instillation are
only one-tenth of those after jejunal instillation.61
Moreover, following administration of a single dose of
either a delayed-release or an azo-bonded formulation,
only approximately 20% of the 5-ASA is taken up systemically (assessed by analysis of 5-ASA and its main
metabolite N-Ac-5-ASA in urine).62
Although there are limits to the utility of plasma PK
and PD assessments for 5-ASA in the treatment of UC,
they have more relevance in the context of avoiding
toxicity as systemic exposure of active drug and its
metabolites drive the occurrence of adverse events
outside the GI tract. PK and PD assessments can often
act as a bridge between nonclinical and clinical safety
evaluation. Indeed, they have been used successfully
in supportive safety analyses in dose-ranging studies.61, 63 In the case of 5-ASA, it is important that such
PK analyses be determined following multiple
doses, as steady-state 5-ASA plasma concentrations

668 G . R . L I C H T E N S T E I N and M . A . K A M M

are several-fold higher than following administration

of a single dose.64
The results of plasma PK analyses of delayed-release
formulations of 5-ASA have shown high inter-patient
variability,65 mainly because of the low bioavailability
of 5-ASA. As most PK studies use only small sample
sizes, making definitive conclusions is difficult. Nevertheless, in a number of studies, 5-ASA formulations
have been compared on the basis of plasma PK
data.62, 6468 While similar 5-ASA plasma PK profiles
may potentially predict similar safety profiles, conclusions regarding efficacy, dosing schedules or colonic
release characteristics of 5-ASA should be considered
with caution. Indeed, as it is the local effect of mesalazine that determines efficacy, not systemic concentration, only well-controlled clinical trials can determine
efficacious doses and or dose regimens.
As plasma PK is not directly related to the availability
of 5-ASA at the colonic mucosa, bioequivalence studies,
which can be used for many drugs to validate potential
therapeutic equivalence, are not appropriate for
delayed-release 5-ASA formulations. Indeed, the FDA
have specifically recommended that bioequivalence
where the drug substance produces its effects by local
action in the GI tract.can be achieved using bioequivalence studies with clinical efficacy and safety endpoints and or suitably designed and validated in-vitro
studies if the latter studies are either reflective of important clinical effects or are more sensitive to changes in
product performance compared to a clinical study.69 In
addition, the European regulatory authorities (Committee of Proprietary Medical Products) have stated that for
locally acting products PK bioequivalence generally is
not a suitable way to show therapeutic equivalence,
since plasma levels are not relevant for local efficacy,
although they may play a role with regard to safety.70
This said, several generic balsalazide formulations have
been approved on the basis of bioequivalence to the
original product Colazide (Salix Pharmaceuticals, Inc.,
Morrisville, NC, USA). It is assumed that the fact that
these were all formulations of an identical prodrug was
pivotal to this decision. Otherwise, no two 5-ASA formulations and specifically no two formulations delivering the drug by different technologies are currently
considered to be bioequivalent.

Mucosal tissue concentrations

The concentration of 5-ASA in mucosal tissues can be
assessed from biopsy samples. Although useful, this

technique is fraught with difficulties and is prone to

large inter- and intra-patient variability. Because of its
invasive nature (requiring endoscopy with mucosal
biopsy), direct assessment of mucosal concentration is
not always feasible in randomized studies. Further,
indirect techniques are also described below. Studies
that have been performed using mucosal biopsy have
shown that high mucosal 5-ASA concentrations are
associated with improved mucosal healing in patients
with UC.45, 71, 72 In a study of 21 patients with UC taking oral 5-ASA therapy, mucosal concentrations of 5ASA were found to be significantly higher in patients
with no or only mild mucosal damage on endoscopy
compared with those having moderate or severe mucosal damage. While this may reflect greater mucosal
5-ASA uptake, it may also reflect the decreased epithelial cell turnover that is seen as healing occurs. It
has also been shown that levels of soluble IL-2 receptor, a pro-inflammatory marker, were lower in patients
with relatively high mucosal 5-ASA concentrations.71
The association between high mucosal 5-ASA levels
and low disease activity was also shown when assessing 5-ASA concentrations from rectal biopsies in a
study of 29 patients taking oral sulfasalazine, or
delayed-release 5-ASA, with or without rectally
administered 5-ASA.45 The link between mucosal
5-ASA levels and disease activity was strengthened
further by the results from a study of 18 patients with
UC deemed at high risk of relapse, despite existing
5-ASA therapy. Following increases in the total daily
5-ASA dose (using both oral and rectal formulations),
significant increases in mucosal 5-ASA concentrations
were observed relative to baseline. Significant reductions in the number of relapses were also seen during
the period of the study.72
Differences in tablet delivery systems, as well as in
intestinal behaviour and colonic segmental transit time,
may lead to differences in drug availability at the level
of the colonic mucosa as assessed by tissue
biopsy.22, 73, 74 For example, De Vos et al.22 reported
that in 61 patients with irritable bowel syndrome in
whom GI transit had been accelerated by the administration of a promotility agent (metoclopramide), higher
mucosal concentrations were achieved after administration of slow release 5-ASA preparations than after
azo-bound drugs. The authors also drew attention to the
fact that an administered dose of 5-ASA may show high
interindividual variability in mucosal concentrations.22
Increasing the oral dose of some 5-ASA formulations
may not necessarily lead to a corresponding increase in
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mucosal concentrations at the sites of inflammation,

irrespective of increasing plasma concentrations.75
These observations could be related to the release of 5ASA from most bolus-release formulations in the terminal ileum or proximal colon. Indeed, studies with a
range of azo-bonded and bolus-release formulations
have shown that mucosal 5-ASA concentrations were
typically highest in the right-sided colon, whereas in
the rectum (a site affected in the majority of patients),
the concentration of 5-ASA was much lower.22, 23 The
uptake of majority of 5-ASA in the terminal ileum or
proximal colon may explain why increased oral dosing
with some formulations only leads to a limited dose
response in 5-ASA levels in the rectum, assessed by rectal mucosal biopsies,22, 75 despite a progressive increase
in serum and urine 5-ASA concentrations.22, 75 Conversely, there are data to suggest that some formulations
may be able to achieve a greater mucosal concentration
following higher oral doses. For example, in a recent
pilot study, higher 5-ASA mucosal concentrations were
observed in the sigmoid colon and rectum in patients
with UC following treatment with MMX mesalazine
4.8 g day given once daily than following treatment
with MMX mesalazine 1.2 or 2.4 g day given once
daily.63 In a biopsy study of patients taking either a
mean dose of 6.75 mg day balsalazide (containing
2.4 g of 5-ASA) vs. patients taking a mean dose of
3.74 g day Asacol, patients in the balsalazide group
demonstrated similar or higher mucosal concentrations
of 5-ASA.76 Taken together, all these findings suggest
that the relationship between dose and mucosal concentrations may be formulation-dependent and independent of relationships between dose and plasma
concentrations.
Interindividual variability in mucosal 5-ASA concentrations may contribute to the variability in clinical
effectiveness that is often observed with oral 5-ASA
therapy. In-vivo studies have shown that the same oral
dose does not always exert the same therapeutic effect
and that increasing the oral dose does not always provide additional therapeutic benefit to all patients.7780
The source of the interindividual variability is unclear,
but may involve differences in drug disposition in the
colonic lumen and mucosa. Factors such as local pH
conditions, transit rates and activities of the relevant
enzymes and transporters responsible for colonic mucosal 5-ASA metabolism and apical secretion back into
the colonic lumen may all be relevant factors. Clearly,
lower tissue 5-ASA concentrations during maintenance
therapy may predispose patients to relapse. Simply
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increasing the oral dose, however, may not be sufficient

to maintain or improve remission rates.

Dialysis
Some investigations have attempted to estimate the
concentration of 5-ASA in mucosal tissues from the faecal concentrations of 5-ASA and its major metabolite
N-Ac-5-ASA. Patients are required to swallow dialysis
bags which are subsequently excreted with the faeces.
Analysis, of such dialysis bags has provided some useful
information about the PK of the aminosalicylates.81
However, collection and analysis of faeces and dialysis bags is unpleasant for patients and technicians.
Furthermore, the stability of compounds released from
the mucosa in stored faeces (or dialysis fluid) is uncertain. Techniques that examine faecal concentrations
therefore seem unlikely to achieve widespread application in clinical practice or trials.
Similarly, in-vivo rectal dialysis utilizes a cylindrical
dialysis membrane that is inserted into the rectum in
contact with the rectal mucosa. Compounds that are
released from the mucosa move across the dialysis
membrane into the dialysis fluid. As previously, their
concentration is measured after removal of the dialysis
bag. This in-vivo technique has been used to study the
effects of 5-ASA82 and insertion of the dialysis bag
does not appear to alter mucosal function unless the
procedure is repeated frequently within a short period.83 However, if equilibrium dialysis is to be performed, the procedure can take 4 h.84
While dialysis presents a potentially less invasive
option than mucosal biopsy, the technique is hampered
by the possibility of degradation or faecal contamination. Furthermore, large molecular weight compounds
may have increased difficulty in entering the dialysis
bag, thus providing an inaccurate representation of the
mucosal concentrations. Importantly, rectal dialysis is
not representative of the mucosal concentrations in
locations other than the rectum. In contrast, faecal dialysis cannot accurately represent any one segment of the
mucosae and indeed may be prone to interference from
the latest delayed-release 5-ASA formulations.

CONCLUSIONS
There are a number of techniques that can be used
to gain information on the relative bioaccessibility and
bioavailability of 5-ASA from different oral formulations. However, all these methods have limitations

670 G . R . L I C H T E N S T E I N and M . A . K A M M

Table 1. Advantages and drawbacks of techniques for studying 5-ASA release

Technique

Advantages

Drawbacks

Simulated GI models

Cannot fully simulate the complexity of the

GI tract physiology

Plasma PK

Allows 5-ASA release to be accurately

assessed over the length of the simulated
GI tract. Allows comparison of different
formulations
Provides information about formulation
disintegration in vivo
Provides supportive data for safety assessments

Determination of 5-ASA
in mucosal biopsies

Mucosal 5-ASA levels shown to be related to

mucosal healing

Faecal rectal dialysis

Allows the assessment of 5-ASA

N-acetyl-5-ASA concentrations at the
colonic mucosa and is less invasive
than endoscopy

Gamma-scintigraphy

May not accurately represent drug release and or

distribution in the GI tract
Not related to the availability of 5-ASA at the
colonic mucosa level
Invasive procedure; considerable inter- and
intra-patient variability in results. More data
are required to validate mucosal 5-ASA
concentrations as a surrogate for clinical efficacy
Unpleasant procedure for patients and technicians.
Potentially susceptible to long-term stability
problems. Not representative of specific
regions entire colon

5-ASA, 5-aminosalicylic acid; GI, gastrointestinal; PK, pharmacokinetics.

(Table 1) and findings from these studies should be

interpreted with caution. Although the methods
described in this review provide interesting data,
which may help us compare specific attributes of various 5-ASA formulations, only adequately powered
clinical efficacy studies in UC patients can determine
the dosing regimen for each 5-ASA medication, which
will lead to maximal clinical effectiveness.

ACKNOWLEDGEMENTS
Declaration of personal interests: Gary Lichtenstein
has served as a speaker, a consultant and an

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