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Mesalazine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Chronic Inflammatory Bowel Disease

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Summary

Synopsis

Mesalazine (5- aminosalicylic acid; mesalamine), the active moiety of sulphasalazine (salazosulfapyridine), is available in specially formulated oral and rectal forms for the treatment of active ulcerative colitis of mild to moderate severity and for maintenance therapy during disease remission. Tablets or capsules coated with acrylic-based resin and tablets containing microgranules coated with ethylcellulose deliver mesalazine to the distal small intestine and colon, thus avoiding the need for the carrier, sulphapyridine, which is responsible for many of the adverse effects associated with sulphasalazine. Since mesalazine is released in the small intestine from some coated preparations in contrast to sulphasalazine, these oral formulations have therapeutic potential in Crohn’s disease.

A limited number of therapeutic trials suggest that orally administered mesalazine 1.5 to 2.4g daily is of similar efficacy to sulphasalazine 2 to 3g daily in patients with mild to moderate ulcerative colitis. The efficacy of mesalazine enemas has been more widely investigated, a dose of 1 to 4g once daily being consistently more effective than placebo and apparently similar to enemas of prednisone 25mg or oral sulphasalazine 3g. Initial results suggest that mesalazine 4g enemas may be more effective than those containing hydrocortisone 100mg. Mesalazine and sulphasalazine in approximately equivalent oral dosages are similarly effective in maintaining remission in ulcerative colitis.

Orally administered coated mesalazine is generally well tolerated by about 85% of patients allergic to or intolerant of sulphasalazine, the remainder experiencing similar reactions to both drugs. Adverse effects of mesalazine enemas are confined to local irritation and effects resulting from enema-tip insertion. Thus, orally administered coated mesalazine is a suitable alternative to sulphasalazine in the treatment of patients with mild to moderate active distal ulcerative colitis and for maintaining remission particularly in patients allergic to or intolerant of sulphasalazine. In patients who find enema therapy acceptable, mesalazine enemas are effective and well tolerated.

Rationale for Using Mesalazine

Mesalazine (5-aminosalicylic acid) has been shown to be the active moiety of sulphasalazine in inflammatory bowel disease, while sulphapyridine acts as a carrier to the colon where the diazo bond is split by bacteria and mesalazine released. Sulphapyridine exerts little, if any, therapeutic effect in ulcerative colitis but is absorbed and apparently causes many of the adverse effects associated with sulphasalazine treatment. However, mesalazine is absorbed quickly from the small intestine when administered orally and may not reach the colon in sufficient amounts to be effective. Thus, in order to reach the colon in therapeutic quantities, mesalazine has to be coated (see pharmacokinetic properties) to deliver mesalazine to the small and large bowel, where it exerts a local effect. Mesalazine may also be delivered to the colon by replacing sulphapyridine with another carrier, as has been done with olsalazine, ipsalazine and balsalazine, although these compounds, like sulphasalazine, rely on bacterial splitting of the nitrogen bond for the release of mesalazine.

Pharmacodynamic Studies

The effect of mesalazine in protecting against or in attenuating the pathophysiological changes in experimental colitis has varied with the animal model chosen. Intraperitoneally administered mesalazine 30 and 340 mg/kg daily was similar in efficacy to prednisolone 4 to 550 mg/kg daily given by the same route and to orally administered sulphasalazine 0.34 to 5 mg/kg in mice with immune complex-induced colitis. Mesalazine 5 mmol/L and sulphasalazine 1.5 mmol/L reversed the increase in water and chloride secretion and the decrease in sodium absorption in dinitrochlorbenzene-induced colitis in guinea-pigs, whereas sulphasalazine, but not mesalazine, reduced ulceration in carrageenan-induced colitis.

Mechanism of Action

The precise mechanism of action of mesalazine is still not known. In vitro studies of fresh biopsies of colonic mucosa from patients with chronic inflammatory bowel disease indicated elevated concentrations of prostaglandin E2, leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acids (HETE), and thus many lines of investigation have been concerned with potential modulation of chemical mediators of the inflammatory response, predominantly arachidonic acid metabolites. The return of elevated prostaglandin E2 concentrations towards normal with remission of inflammatory bowel disease supports the role of prostaglandins and their metabolites, via the cyclo-oxygenase pathway, in the pathogenesis of inflammatory bowel disease. However, the failure of mesalazine to influence concentrations of prostaglandin metabolites in some studies and their inhibition by indomethacin, which is ineffective in treating inflammatory bowel disease, cast doubt on this hypothesis. Evidence is accumulating that leukotrienes may be the principal mediators of inflammation in patients with inflammatory bowel disease. LTB4 release into the rectal lumen is elevated in patients with ulcerative colitis and attenuated by mesalazine and prednisone. Sulphasalazine and mesalazine inhibited migration of intestinal macrophages to LTB4 and thus may limit intestinal inflammation by restricting migration of macrophages to inflamed areas. It has also been suggested that mesalazine may act as a radical scavenger against reactive oxygen moieties or it may act as a suppressor of fatty acid peroxidation.

Pharmacokinetic Properties

When pure mesalazine is administered directly in the proximal part of the small bowel or orally as a conventional tablet it is rapidly and almost completely absorbed, with little drug reaching the distal small intestine and colon. The problem of premature absorption has been overcome by coating tablets with ‘Eudragit-S’, which allows disintegration when the pH is ⩾ 7, or with ‘Eudragit-L’ which permits disintegration at about pH 5.6, as well as coating microgranules with ethylcellulose resulting in controlled release of mesalazine throughout the gastrointestinal tract. Radiographic tracing of a barium sulphate marker, or monitoring of 111 indium-labelled preparations, has confirmed that the delayed-release compounds are all capable of delivering mesalazine to the distal bowel. Direct instillation of mesalazine into the right or left parts of the colon or into the small intestine has demonstrated greater absorption from the small intestine than from the colon.

The mean maximum plasma concentration of mesalazine in healthy volunteers was 330 μmol/L 5 minutes after intravenous administration of 0.5g compared with 234 μmol/ L 2 hours after an uncoated tablet containing mesalazine 2.4g and 30 μmol/L 6 hours after oral administration of the same dose coated with ‘Eudragit-S’ Plasma concentrations and urinary recovery of mesalazine were similar after oral administration of sulphasalazine 2 to 5g daily and an equivalent dosage of mesalazine coated with ‘Eudragit-S’ in patients with ulcerative colitis in remission.

Unchanged mesalazine is 43% bound to plasma proteins while the acetylated metabolite is 78% protein bound. Volume of distribution was 18 and 25L after intravenous and oral administration of uncoated mesalazine, respectively.

Mesalazine is largely eliminated as its acetylated metabolite, acetylmesalazine, which is excreted predominantly in the urine. The acetylation is not influenced by acetylator phenotype and appears to be irreversible. Urinary recovery of total mesalazine within 4 hours is about 50% after ingestion of uncoated tablets and 13% and 0% after tablets coated with ‘Eudragit-L’ and -‘S’ respectively. Total urinary recovery of mesalazine in these formulations 24 to 48 hours after ingestion was 52%, 55% and 21% of the ingested dose, respectively. Mean faecal excretion of total mesalazine over 7 days tends to be greater in patients with active ulcerative colitis than in those in remission. There is some evidence that mesalazine undergoes a degree of enterohepatic recirculation.

Renal clearance of acetyl mesalazine was 2 to 3 times the glomerular filtration rate, indicating predominant renal tubular secretion.

Plasma elimination half-life of total mesalazine ranged from 0.7 to 2.4 hours in patients with inflammatory bowel disease treated with an enteric-coated form of the drug, while that of the acetylated metabolite was about twice that of mesalazine after intravenous and oral administration.

Therapeutic Trials

Mesalazine, administered orally as coated tablets or capsules, or as retention enemas or suppositories, has been studied in the treatment of active chronic inflammatory bowel disease of mild to moderate severity and as maintenance therapy. Many trials have judged clinical efficacy according to clinical resolution of symptoms, sigmoidoscopic appearance and histological findings, while a few studies have relied largely on clinical criteria. Generally, the study populations have been too small to demonstrate statistically significant differences between treatments of similar efficacy, although sufficiently large to show superiority of mesalazine over placebo.

Non-comparative studies of mesalazine 1.5 to 3.2g daily administered as coated tablets indicated clinical remission in about 64 to 72% of patients with mild to moderate active ulcerative colitis. Favourable results were also recorded in patients with Crohn’s disease and clinical results in a large general practice study involving 1215 patients with ulcerative colitis and 498 with Crohn’s disease were described as ‘very good’ or ‘good’ in 85 to 93% of patients treated with mesalazine. Mesalazine retention enemas have produced clinical improvement in 60 to 87% of generally small numbers of patients studied in non-comparative trials, many of whom had disease unresponsive to previous therapy with sulphasalazine and/or corticosteroids.

In a few trials in patients with active mild to moderate inflammatory bowel disease (ulcerative colitis and Crohn’s disease) orally administered coated mesalazine 2.4 to 4.8g daily has been found significantly more effective than placebo and sulphasalazine 2g daily. However, dosages of 1.5 or 1.6g were not statistically significantly superior to placebo, and not distinguishable from sulphasalazine 3g daily in a well-conducted international study.

Administered once daily as retention enemas containing 1 to 4g, mesalazine was superior to placebo as was a dose of 1.5g daily as suppositories in patients with distal ulcerative colitis. Mesalazine 4g retention enemas were more effective than those containing hydrocortisone 100mg while similar results were obtained using enemas containing mesalazine 1g or prednisone 25mg. Over half of the patients who failed to respond during the first 2 weeks of treatment did so during the next 2 weeks of therapy. Enemas of mesalazine and sulphasalazine of equal strength (1.5g each) indicated a greater efficacy of mesalazine in patients with moderate ulcerative colitis, but mesalazine suppositories (1.5g) and oral sulphasalazine 3g were of similar efficacy in small numbers of patients with ulcerative colitis or Crohn’s disease.

Retention enemas containing mesalazine lg administered once daily were statistically significantly better than placebo in maintaining remission in ulcerative colitis, over a 1-year period. Mesalazine 0.8 to 2.7g daily and sulphasalazine 1.6 to 4g daily were similarly effective in maintaining remission in patients with inactive ulcerative colitis, with 73 to 82% still in remission after 4 to 6 months and 46 to 62% at the end of 1 year. Mesalazine 1.5g daily was superior to placebo in preventing relapse in patients with inactive Crohn’s disease.

Adverse Effects

The most commonly reported adverse effects of mesalazine were headache (up to 13%) and nausea (up to 8%), while itching, dizziness, indigestion, muscular ache and fever have usually occurred in fewer than 5% of patients. However, these effects occurred with similar frequency in patients with ulcerative colitis who received placebo. Furthermore, they did not appear to increase when the dosage of mesalazine was doubled. An idiosyncratic reaction characterised by worsening of symptoms, which resolves on drug withdrawal, has been reported in a few instances. Adverse effects to mesalazine enemas have usually been confined to local irritation or other effects resulting from enema-tip insertion.

Most patients intolerant of, or allergic to, sulphasalazine tolerated mesalazine with minor or no adverse effects. About 10% of these patients experienced similar adverse effects to oral forms of both drugs, but this was more evident in patients who exhibited severe allergic or gastrointestinal reactions to sulphasalazine. Semen abnormalities induced by sulphasalazine improved or were reversed after mesalazine substitution. There has been no evidence of impaired renal function during mesalazine therapy.

Dosage and Administration

In the treatment of chronic inflammatory bowel disease mesalazine may be administered orally as coated products, or rectally as retention enemas or suppositories. The usual dose is 1.5 to 2.4g daily administered orally in 3 divided doses, or 1 to 4g rectally, once daily at bedtime. Remission maintenance dosages have ranged from 0.8 to 3.2g daily administered orally in divided doses, or 1g enemas given once daily.

Patients who have experienced severe allergic reactions to sulphasalazine should be closely observed for similar manifestations when started on mesalazine (see Adverse Effects).

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    Rex N. Brogden & Eugene M. Sorkin

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Various sections of the manuscript reviewed by: S. Bank, Division of Gastroenterology, State University of New York, Long Island Jewish Medical Center, New Hyde Park, New York, USA; M. Campieri, Istituto di Clinica Medica e Gastroenterologia, University of Bologna, Bologna, Italy; E.F. Hvidberg, Department of Clinical Pharmacology, University Hospital, Blegdamsvej, Copenhagen, Denmark; U. Klotz, Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Federal Republic of Germany; P.B. Miner, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA; O.H. Nielsen, Department of Medical Gastroenterology, University of Copenhagen, Herlev, Denmark; P. Prentel, Department of Medicine, Hennepin City Medical Center, Minneapolis, Minnesota, USA; S.N. Rasmussen, Department of Medical Gastroenterology, Aalborg Hospital, Denmark; S.A. Riley, Department of Medicine, University of Manchester, Salford, England; K.W. Schroeder, Department of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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Brogden, R.N., Sorkin, E.M. Mesalazine. Drugs 38, 500–523 (1989). https://doi.org/10.2165/00003495-198938040-00003

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