Enterohepatic circulation of indomethacin and its role in intestinal irritation.

Abstract The accumulative biliary secretion of indomethacin and its conjugate(s), based upon biliary clearance constants and areas portal and peripheral plasma profiles, has been determined for five laboratory species and estimated for man. This parameter, termed Σ bile % , ranges approximately 30-fold from 13 per cent of dosage in the rabbit to 362 per cent in the dog, and provides a quantitative correlate to the wide species variation in sensitivity to indomethacin-related intestinal lesions. Extrapolation of the Σ bile % vs. intestinal toxicity relationship to man predicts a therapeutic ratio of ca. 20:1 with respect to intestinal irritation. The pharmacokinetic modeling derived for the present purpose should be of general utility in the quantitation of enterohepatic recycling of drugs or metabolites whose loci of intended or untoward effects include the liver or gut.