Clinical Pharmacokinetics of Sulphasalazine, Its Metabolites and Other Prodrugs of 5-Aminosalicylic Acid

Abstract

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA) represents the therapeutic moiety of sulphasalazine in the treatment of inflammatory bowel disease. For more than 4 decades, the active metabolite, 5-ASA, has been administered in the form of the 'prodrug' sulphasalazine; however, in contrast to sulphasalazine, the pharmacokinetics of 5-ASA were unknown until recently. Sulphasalazine itself is poorly absorbed (3 to 12%) and its elimination half-life of about 5 to 10 hours is probably affected by the absorption process. The major part of sulphasalazine is split by bacterial azo-reduction in the colon into 5-ASA and sulphapyridine, the latter accounting for most of the adverse effects of sulphasalazine. The effective cleavage of sulphasalazine depends on an intact colon and transit time. It is markedly reduced in patients taking antibiotics and after removal of the large bowel. The formed sulphapyridine is almost completely absorbed and eliminated by hydroxylation, glucuronidation and polymorphic acetylation. Depending on the genetic phenotype, the elimination half-life and apparent oral clearance of sulphapyridine are approximately 14 hours and 40 ml/min (slow acetylators) or 6 hours and 150 ml/min (fast acetylators), respectively. Of the 5-ASA released from its 'vehicle' sulphapyridine in the colon, at least 25% is absorbed and after acetylation is subsequently excreted in the urine. At least 50% is eliminated in the faeces. Recently, 5-ASA has also been administered directly in the form of enemas, suppositories and oral slow-release preparations. While the elimination half-life of 5-ASA is short (0.5 to 1.5 h), its major acetylated metabolite (which may be active) exhibits a half-life of 5 to 10 hours. During therapy with sulphasalazine or 5-ASA, steady-state plasma concentrations of 5-ASA are relatively low (less than or equal to 2 micrograms/ml); thus its mode of action appears to be topically rather than systemically. Another approach to deliver the active 5-ASA to the gastrointestinal tract is accomplished with novel 'prodrugs' of 5-ASA, in which the carrier molecule sulphapyridine is replaced by 5-ASA itself (azodisalicylate) or other compounds.

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“…As anticipated from systemic pharmacokinetics of intrajejunal drug (I) and other observations (16,64), the kinetics of intravenously administered 5-ASA showed that the drug is rapidly cleared from plasma mainly by metabolism (VI). Further.…”

“…proved that the 5-ASA-moiety is a n active drug in its own right (8) which supported early proposals on the possibilities for improving the management of CIBD with SASP (27,82). Thus, a rapid development in the field of new 5-ASA drug-formulations with different principles of sustained-release (SR) is now taking place (16,57,64).…”

“…Further, SASP is not absorbed in any considerable amount in the colon or rectum (3,104). SASP is mainly metabolized by enzymatic azo-reduction which, thus, releases its two components (26,64). Azo-reductase-activity is found in faecal bacterial isolates, the colonic mucosa and the liver (3,9).…”

“…Formulations of sustained release 5-ASA based on coatings with pH-dependant dissolution or diffusion have recently emerged (16,57,64). With these formulations the sulfapyridine-component of SASP and its related side-effects may be avoided (40).…”

“…Since release of 5-ASA is independent of bacterial action treatment of CD with a sterile pre-colonic location in the small intestine is possible (42). Several studies on bio-availability from SR-5-ASA-drugs have been published in recent years (12,57,64). The most important pharmacological properties of a SR-drug preparation with regional effect in the intestine to be considered are: 1) site of release, 2) rate and amount of release of drug, and the resulting regional concentration and hence effect, and 3) systemic bio-availability which may be related to systemic toxicity.…”