PHARMACOKINETICS AND TOXICITY OF HIGH-DOSE TOPICAL COLONIC 5-AMINOSALICYLIC ACID THERAPY IN PATIENTS WITH SEVERELY ACTIVE TOTAL ULCERATIVE-COLITIS

Objective: To investigate the pharmcokinetics and toxicity of high-dos e topical colonic 5-aminosalicylic acid (5-ASA, mesalazine) therapy in patients with severely active total ulcerative colitis. Design: Durin g colonoscopy, a tube was placed through the instrumentation channel i nto the caecum; 4 g 5-ASA (enema) was instilled twice daily through th e tube for 3 weeks. Patients: Eight patients with severely active tota l ulcerative colitis were investigated. Methods: 5-ASA and acetylated 5-ASA were monitored in serum (2 days) and urine (5 days). Colonic tra nsport of Tc-99m-labelled 5-ASA enema was measured by the nuclear imag ing technique on the fifth day. 5-ASA toxicity was clinically and bioc hemically monitored. Results: Colonic absorption (C(max) on day 1, 1.4 +/- 0.3 mug/ml; mean +/-SEM) and urinary excretion (total recovery on day 1, 10.5+/- 1.6%) of 5-ASA were low. The half-life of 5-ASA was lon g (t1/2 4.2+/- 0.9 h) and the percentage of unacetylated urinary 5-ASA (17+/- 2%) was high, suggesting saturation of presystemic 5-ASA acety lation. Dose-corrected absorption, acetylation and excretion rates wer e two- to threefold lower than reported data from patients in remissio n. Regional radioactivity of Tc-99m-labelled 5-ASA enema was high in t he ascending colon (37%) and stool (45%) and low in the transverse (7% ), descending (7%) and rectosigmoid (6%) colon. Clinical and biochemic al monitoring of these eight patients did not reveal any 5-ASA toxicit y. Conclusion: Pharmacokinetics of 5-ASA in patients with severely act ive total ulcerative colitis show low 5-ASA absorption, acetylation an d excretion rates. Colonic transit studies suggest rapid transit of th e enema through the left-sided colon. High-dose topical colonic 5-ASA therapy seems to be possible without significant toxicity.