Clinical Pharmacology of 5-ASA Compounds in Inflammatory Bowel Disease

Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis.

The 5-aminosalicylic acid (5-ASA, mesalamine) class of drugs has been recommended as the first line of therapy in patients with mild to moderate ulcerative colitis (UC). Mesalamine’s mechanism of action is not fully understood, but it has been shown to be successful in the induction and maintenance of clinical remission in patients with UC. Since the discovery of sulfasalazine, there have been several newer preparations of 5-ASA with different modes of delivery on the market, all aimed at minimal systemic absorption and maximal topical application.

Rectal administration of gels, foams, and enemas containing 5-ASA is the most effective way to achieve maximal topical efficacy. Topical mesalamine has been demonstrated to be effective in treating patients with active proctosigmoiditis and left-sided colitis. However, patient tolerability of rectal administration is poor because of difficulty in administration, problems with retention and leakage, and patient discomfort. Thus, despite evidence suggesting a superiority of topical mesalamine to oral aminosalicylates alone in achieving clinical improvement in patients with mild to moderate distal colitis, the therapeutic plan is often guided largely by patient preferences with the oral route of administration preferred over rectal therapy. Oral 5-ASA in its unformulated form is rapidly absorbed in the small intestine, leaving a minimal concentration of drug to treat the colon ( Fig. 1 ). Various formulations have thus been manufactured to ensure maximal delivery of 5-ASA to the site of inflammation. Sulfasalazine, olsalazine, and balsalazide are azo-bonded prodrugs, in which 5-ASA (the active moiety) is linked by an azo bond to the carrier moiety ( Fig. 2 ). The bond is cleaved by colonic bacterial azoreductase, resulting in release of the 2 constituent moieties. Other oral formulations such as Asacol, which is coated with a gastroresistant and a pH-sensitive acrylic-based resin (Eudragit-S), delay release of the drug until it reaches the terminal ileum, where the pH is consistently 7 or higher. Similarly, Apriso also consists of a delayed-release mechanism and offers once-daily dosing with a capsule containing granules composed of mesalamine in a polymer matrix with an enteric (outer) coating, Eudragit-L. The outer coating dissolves in the terminal ileum (pH ≥6), while the polymer matrix core facilitates slow, sustained release throughout the colon ( Fig. 3 ). Pentasa, formulated as ethylcellulose-coated controlled-release capsules, is released throughout the gastrointestinal tract. Lialda contains a “Multi Matrix System Technology” (MMX) with lipophilic and hydrophilic matrices to provide delayed release of mesalamine. Lialda contains Eudragit-S, which enables mesalamine release at pH 7 or higher in the terminal ileum, and its release continues throughout the colon. Despite the variety of delivery mechanisms employed, the results of clinical trials have shown the efficacy of historically available oral formulations to be broadly similar. This review focuses on a more detailed discussion of the various 5-ASA preparations and release formulations, to guide physicians in the clinical decisions regarding choice of drug.