A theoretical examination of the effects of gut wall metabolism,hepatic elimination,and enterohepatic recycling on estimates of bioavailability and of hepatic blood flow

A model including two eliminating compartments (the liver and the gastrointestinal mucosa) and a noneliminating compartment (the blood or central compartment) was developed to predict the effects of hepatic elimination, gastrointestinal mucosal metabolism, and the occurrence of enterohepatic recycling of a drug and its metabolites on the area under the blood concentrationtime curve (AUC). Several limiting cases where complete absorption or complete or nonexistent enterohepatic recycling of a drug and its metabolite occurred were only considered. Under linear kinetic conditions, the occurrence of hepatic elimination and enterohepatic recycling of a drug and its metabolite in the absence of intestinal mucosal metabolism should affect only the area under the curve and not the availability for both the intraperitoneal and the oral dose. In the presence of intestinal mucosal metabolism, the area under the curve should change with different routes of administration; a larger area, hence a higher availability, should occur after intraperitoneal administration than after oral administration of the drug. For a drug which is eliminated solely by the liver, apparent hepatic flow can be estimated by the dose divided by the difference in the area under the curve for an intravenous dose and the area under the curve for the same intraperitoneal or oral dose. In the absence of gastrointestinal mucosal metabolism, the presence of enterohepatic recycling of a drug and its metabolite should not affect the estimation of apparent hepatic blood flow. However, when gastrointestinal mucosal metabolism is present, there should be an overestimation of hepatic flow when AUC_i.p. and AUC_i.v. are used and a slight underestimation of hepatic flow when AUC_i.v. and AUC_p.o. are used.