Generalized consideration of administration route dependence of drug disposition and use of urinary data for prediction of the dependence.

Abstract

Route dependence of area under blood (or plasma) concentration curve (AUC) of drug, or first-pass effect was considered based on a generalized perfusion model where drug is supposed to be disposed in liver and kidney. The results verified the Gibaldi's equation based on a three compartment model to describe the route dependence with hepatic blood flow and hepatic clearance. From this consideration, the equation to described and to predict the dose dependence of AUC with urinary excretion and only one blood concentration at a steady state during a constant infusion was proposed and verified experimentally. And further the correspondence of the generalized perfusion model to a multi-compartment mammillary model for AUC was discussed and the equation for the route dependence was proposed in the case in which drug circulates through enterohepatic system and is disposed in small intestine as well as in liver and kidney.