RESUMO
BACKGROUND: Mesalazine (5-ASA) is a standard treatment for ulcerative colitis. Extent of absorption and N-acetylation determine systemic exposure to 5-ASA, and are thereby relevant for the safety of the treatment. The aim of the study was to compare absorption and N-acetylation of 5-ASA following rectal or oral drug administration. Healthy subjects were compared to patients with ulcerative colitis to evaluate the impact of chronic inflammation of colorectal mucosa on disposition of 5-ASA. MATERIALS AND METHODS: First, 12 healthy adults were randomized to receive 2 g of 5-ASA by each of four different formulations: oral delayed release granules, 30 mL enema, 60 mL rectal foam, and 120 mL rectal foam. Second, 12 patients with active ulcerative colitis received 60 mL rectal foam. Pharmacokinetic analysis was performed by determination of 5-ASA and its acetylated, pharmacologically inactive metabolite (Ac-5-ASA) in plasma and urine. RESULTS: First, systemic exposure to 5-ASA was markedly lower after rectal drug administration as compared to oral dosing (P < 0.001; e.g. median relative bioavailability of 60 mL rectal foam: 36%). Second, N-acetylation of rectal 5-ASA was lower in patients than in healthy subjects [area under the curve (AUC) ratio Ac-5-ASA/5-ASA: 1.6 +/- 0.5 vs. 2.3 +/- 0.4, mean +/- SD, P < 0.01]. High peak plasma concentrations of 5-ASA were correlated with high microscopic disease activity (r = 0.67, P < 0.05). CONCLUSIONS: Rectal delivery of 5-ASA results in low systemic drug exposure with potentially reduced toxicity in comparison with oral drug administration. Chronic inflammation of colorectal mucosa might be a relevant source of variability in pharmacokinetics of 5-ASA.