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) concentrations curve (AUC) of drug or 1st-pass effect was considered based on a generalized perfusion model, where drug is supposed to be disposed in liver and kidney. Gibaldi''s equation based on a 3 compartment model to describe route dependence with hepatic blood flow and hepatic clearance was verified. From this consideration, the equation to describe and predict dose dependence of AUC with urinary excretion and only 1 blood concentration at a steady state during a constant infusion was proposed and verified experimentally [in rats with phenosulfophthalein administration]. The correspondence of the generalized perfusion model to a multi-compartment mammillary model for AUC was discussed, with the equation for the route dependence was proposed in the case in which drug circulates through enterohepatic system and is disposed in small intestine, liver and kidney.