To investigate the pharmcokinetics and toxicity of high-dose topical colonic 5-aminosalicylic acid (5-ASA, mesalazine) therapy in patients with severely active total ulcerative colitis.Design:
During colonoscopy, a tube was placed through the instrumentation channel into the caecum; 4 g 5-ASA (enema) was instil led twice daily through the tube for 3 weeks.Patients:
Eight patients with severely active total ulcerative colitis were investigated.Methods:
5-ASA and acetylated 5-ASA were monitored in serum (2 days) and urine (5 days). Colonic transport of Tc99m-labelled 5-ASA enema was measured by the nuclear imaging technique on the fifth day. 5-ASA toxicity was clinically and biochemically monitored.Results:
Colonic absorption (Cmax on day 1, 1.4 ± 0.3μg/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 long (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 acetylation. Dose-corrected absorption, acetylation and excretion rates were two- to threefold lower than reported data from patients in remission. Regional radioactivity of Tc99m-labelled 5-ASA enema was high in the ascending colon (37%) and stool (45%) and low in the transverse (7%), descending (7%) and rectosigmoid (6%) colon. Clinical and biochemical monitoring of these eight patients did not reveal any 5-ASA toxicity.Conclusion:
Pharmacokinetics of 5-ASA in patients with severely active total ulcerative colitis show low 5-ASA absorption, acetylation and excretion rates. Colonic transit studies suggest rapid transit of the enema through the left-sided colon. High-dose topical colonic 5-ASA therapy seems to be possible without significant toxicity.