Abstract

Venlafaxine (VEN), a drug used in the treatment of depression, undergoes significant first-pass metabolism after oral dosing toO-desmethylvenlafaxine (ODV), a metabolite with comparable therapeutic activity to that of parent drug. The pharmacokinetic disposition of VEN was characterized using a “first-pass” model that incorporates a presystemic compartment (liver) to account for the first-pass metabolism of VEN to ODV. A series of differential equations were simultaneously fitted to plasma concentrations of parent and metabolite. A good fit of the model to observed data was demonstrated, generating estimates for the following parameters:k_a (1.31 ± 0.009 hr⁻¹),V_VEN (252 ± 87.6 liters),CL_int (65.8 ± 39.7 liters/hr),R_L (liver:plasma partition coefficient, 29.6 ± 18.3), V_ODV (181 ± 84.1 liters), and CL_ODV (23.5 ± 12.5 liters/hr). Parameter estimates correlated closely with those obtained through noncompartmental methods. These results indicate that the time-course disposition of a compound undergoing first-pass hepatic metabolism after oral dosing can be successfully modeled.