DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

sulfapyridine
(metabolite)
sulfasalazine
olsalazine
mesalamine (5-ASA)
(the active drug)
N-acetyl-5-ASA
(metabolite)
basalazide
4-ABA
(metabolite)
Figure 47–3. Metabolic fates of the different oral formulations
of mesalamine (5-ASA). Chemical structures are in Figure 47–2.
(balsalazide, COLAZIDE). Thus, these compounds act at
sites along the GI tract similar to those of sulfasalazine.
The alternative approaches employ either a delayedrelease
formulation (PENTASA) or a pH- sensitive coating
(ASACOL; LIALDA/MEZAVANT). Delayed-release mesalamine
is released throughout the small intestine and colon,
whereas pH- sensitive mesalamine is released in the terminal
ileum and colon. These different distributions of
drug delivery have potential therapeutic implications.
Oral sulfasalazine is effective in patients with mild or moderately
active ulcerative colitis, with response rates in the range of
60-80% (Prantera et al., 1999). The usual dose is 4 g/day in four
divided doses with food; to avoid adverse effects, the dose is
increased gradually from an initial dose of 500 mg twice a day.
Doses as high as 6 g/day can be used but cause an increased incidence
of side effects. For patients with severe colitis, sulfasalazine
is of less certain value, even though it is often added as an adjunct
to systemic glucocorticoids. Regardless of disease severity, the drug
plays a useful role in preventing relapses once remission has been
achieved. In general, newer 5-ASA preparations have similar therapeutic
efficacy in ulcerative colitis with fewer side effects. Because
they lack the dose- related side effects of sulfapyridine, the newer
formulations can be used to provide higher doses of mesalamine with
some improvement in disease control. The usual doses to treat active
disease are 800 mg three times a day for ASACOL and 1 g four times
a day for PENTASA. Lower doses are used for maintenance (e.g.,
ASACOL, 800 mg twice a day). Although some studies have suggested
that a given preparation may be superior in treating colonic disease,
there is no consensus on this issue.
The efficacy of 5-ASA preparations (e.g., sulfasalazine) in
Crohn’s disease is less striking, with modest benefit at best in controlled
trials. Sulfasalazine has not been shown to be effective in
maintaining remission and has been replaced by newer 5-ASA
preparations. Some studies have reported that both ASACOL and PEN-
TASA are more effective than placebo in inducing remission in
patients with Crohn’s disease (particularly colitis), although higher
doses than those typically used in ulcerative colitis are required. The
role of mesalamine in maintenance therapy for Crohn’s disease is
controversial, and there is no clear benefit of continued 5-ASA therapy
in patients who achieve medical remission (Camma et al., 1997).
Because they largely bypass the small intestine, the secondgeneration
5-ASA prodrugs such as olsalazine and balsalazide do
not have a significant effect in small- bowel Crohn’s disease.
Topical preparations of mesalamine suspended in a wax
matrix suppository (ROWASA) or in a suspension enema (CANASA) are
effective in active proctitis and distal ulcerative colitis, respectively.
They appear to be superior to topical hydrocortisone in this setting,
with response rates of 75-90%. Mesalamine enemas (4 g/60 mL)
should be used at bedtime and retained for at least 8 hours; the suppository
(500 mg) should be used two to three times a day with the
objective of retaining it for at least 3 hours. Response to local therapy
with mesalamine may occur within 3-21 days; however, the
usual course of therapy is from 3-6 weeks. Once remission has
occurred, lower doses are used for maintenance.
Pharmacokinetics. Approximately 20-30% of orally administered
sulfasalazine is absorbed in the small intestine. Much of this is taken
up by the liver and excreted unmetabolized in the bile; the rest
(~10%) is excreted unchanged in the urine. The remaining 70%
reaches the colon, where, if cleaved completely by bacterial
enzymes, it generates 400 mg mesalamine for every gram of the parent
compound. Thereafter, the individual components of sulfasalazine
follow different metabolic pathways. Sulfapyridine, which
is highly lipid soluble, is absorbed rapidly from the colon. It undergoes
extensive hepatic metabolism, including acetylation and
hydroxylation, conjugation with glucuronic acid, and excretion in
the urine. The acetylation phenotype of the patient determines
plasma levels of sulfapyridine and the probability of side effects;
STOMACH JEJUNUM ILEUM COLON
1355
CHAPTER 47
PHARMACOTHERAPY OF INFLAMMATORY BOWEL DISEASE
Sulfasalazine
Olsalazine (DIPENTUM)
Mesalamine pH-sensitive Release Tablets (ASACOL/LIALDA)
Mesalamine Delayed Release Capsules (PENTASA)
Figure 47–4. Sites of release of mesalamine (5-ASA) in the GI tract from different oral formulations.