Active metabolites formed during hepatic first-pass: simulations featuring their contribution to the overall effect in altered liver clearance and drug-drug interactions

Background Phase I and occasionally also phase II metabolites may contribute to the overall effect of a drug. This is not always apparent or revealed, since total concentrations of metabolites may be low in relation to parent drug concentrations. In the case of carvedilol, using a comparison of HPLC and β1-specific radioligand receptor binding assay (RRA), it was possible to demonstrate that regarding βadrenoceptor blockade the effect appears directly linked to the serum compartment, which indicates instantaneous equilibrium between the blood compartment and the biophase, and that oxidative metabolites significantly contribute to the effect, particularly after oral administration. This drug serves as model compound in different approaches for evaluating the role of formation of active metabolites during first-pass when hepatic clearance varies.