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, undergoes significant first-pass metabolism after oral dosing to O-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.
Taft
D R
DR
Division of Pharmaceutics and Industrial Pharmacy, Long Island University, Brooklyn, NY 11201, USA.
Iyer
G R
GR
Behar
L
L
DiGregorio
R V
RV
D000284:Administration, Oral; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003511:Cyclohexanols / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*; D000069470:Venlafaxine Hydrochloride
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride