Drugs Used in the Treatment of Gastrointestinal Diseases 1107 work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5-ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine.
1.
Azo compounds—Sulfasalazine, balsalazide, and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule (Figure 62–8). In sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide, 5-ASA is bound to 4-aminobenzoyl-β-alanine; and in olsalazine, two 5-ASA molecules are bound together. The azo structure markedly reduces absorption of the parent drug from the small intestine. In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azoreductase enzyme, releasing the active 5-ASA. Consequently, high concentrations of active drug are made available in the terminal ileum or colon.
2.
Mesalamine compounds—Other proprietary formulations have been designed that package 5-ASA itself in various ways to deliver it to different segments of the small or large bowel. These 5-ASA formulations are known generically as mesalamine. Pentasa is a mesalamine formulation that contains timed-release microgranules that release 5-ASA throughout the small intestine (Figure 62–9). Asacol and Apriso have 5-ASA coated in a pH-sensitive resin that dissolves at pH 6–7 (the pH of the distal ileum and proximal colon). Lialda also uses a pH-dependent resin that encases a multimatrix core. On dissolution of the pH-sensitive resin in the colon, water slowly penetrates its hydrophilic and lipophilic core, leading to slow release of mesalamine throughout
FIGURE 62–8 Chemical structures and metabolism of aminosalicylates. Azo compounds (balsalazide, olsalazine, sulfasalazine) are converted by bacterial azoreductase to 5-aminosalicylic acid (mesalamine), the active therapeutic moiety.
Sulfasalazine Balsalazide 5-ASA pH-dependent release (Asacol, Lialda) 5-ASA delayed-release capsules (Pentasa)
FIGURE 62–9 Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.
the colon. 5-ASA also may be delivered in high concentrations to the rectum and sigmoid colon by means of enema formulations (Rowasa) or suppositories (Canasa).
Although unformulated 5-ASA is readily absorbed from the small intestine, absorption of 5-ASA from the colon is extremely low. In contrast, approximately 20–30% of 5-ASA from current oral mesalamine formulations is systemically absorbed in the small intestine. Absorbed 5-ASA undergoes N-acetylation in the gut epithelium and liver to a metabolite that does not possess significant anti-inflammatory activity. The acetylated metabolite is excreted by the kidneys.