RT Journal Article
SR Electronic
T1 Application of a First-Pass Effect Model to Characterize the Pharmacokinetic Disposition of Venlafaxine after Oral Administration to Human Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1215
OP 1218
VO 25
IS 10
A1 David R. Taft
A1 Ganesh R. Iyer
A1 Leon Behar
A1 Robert V. Digregorio
YR 1997
UL http://dmd.aspetjournals.org/content/25/10/1215.abstract
AB 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:ka (1.31 ± 0.009 hr−1),VVEN (252 ± 87.6 liters),CLint (65.8 ± 39.7 liters/hr),RL (liver:plasma partition coefficient, 29.6 ± 18.3), VODV (181 ± 84.1 liters), and CLODV (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. The American Society for Pharmacology and Experimental Therapeutics