APPLICATION OF A FIRST-PASS EFFECT MODEL TO CHARACTERIZE THE PHARMACOKINETIC DISPOSITION OF VENLAFAXINE AFTER ORAL-ADMINISTRATION TO HUMAN-SUBJECTS

Venlafaxine (VEN), a drug used in the treatment of depression, undergo es significant first-pass metabolism after oral dosing to O-desmethylv enlafaxine (ODV), a metabolite with comparable therapeutic activity to that of parent drug. The pharmacokinetic disposition of VEN was chara cterized 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 mod el to observed data was demonstrated, generating estimates for the fol lowing parameters: k(a) (1.31 +/- 0.009 hr(-1)), V-VEN (252 +/- 87.6 l iters), CLint (65.8 +/- 39.7 liters/hr), R-L (liver:plasma partition c oefficient, 29.6 +/- 18.3), V-ODV (181 +/- 84.1 liters), and CLODV (23 .5 +/- 12.5 liters/hr). Parameter estimates correlated closely with th ose obtained through noncompartmental methods. These results indicate that the time-course disposition of a compound undergoing first-pass h epatic metabolism after oral dosing can be successfully modeled.