INVIVO INTESTINAL METABOLISM OF 7-ETHOXYCOUMARIN IN THE RAT - PRODUCTION AND DISTRIBUTION OF PHASE-I AND PHASE-II METABOLITES IN THE ISOLATED, PERFUSED INTESTINAL LOOP

These studies describe the phase I and II metabolism of 7-ethoxycoumarin (7-EC) in the isolated, perfused intestinal loop. Following cytochrome P450-dependent oxidative deethylation of 7-EC by intestinal epithelial cells, the product, 7-hydroxycoumarin (7-HC), undergoes phase II conjugation to form both the glucuronide and sulfate conjugates. The capacity for conjugation of 7-HC within the intestinal epithelium exceeds that of phase I oxidative deethylation, as demonstrated by the absence of increased release of unconjugated 7-HC upon saturation of the conjugation pathways. The formation of both glucuronide (53-62%) and sulfate (41-43%) conjugates contributed to a comparable extent to the overall phase II metabolism of 7-HC within the intestine. This is in contrast to the liver, where sulfate conjugation has been shown to be the predominant phase II metabolic pathway. Furthermore, it was found that unconjugated and sulfate conjugated 7-HC were evenly distributed between the lumenal perfusate and blood compartments, whereas the glucuronide conjugates of 7-HC were preferentially transported at a 4:1 ratio toward the blood. These results indicate that the epithelial cells of the small intestine have the capacity to biotransform orally administered xenobiotics, and the ultimate profile of metabolites generated may influence the biodisposition of these compounds. © 1991.