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: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.
Footnotes
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Send reprint requests to: Dr. David R. Taft, Division of Pharmaceutics and Industrial Pharmacy, Long Island University, 1 University Plaza, Brooklyn, NY 11201.
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Received March 5, 1997; accepted June 11, 1997.
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↵2 S. Troy, Wyeth-Ayerst Research, personal communication.
- Abbreviations used are::
- VEN
- venlafaxine
- ODV
- O-desmethylvenlafaxine
- IS
- internal standard
- AUC
- area under the plasma concentration vs. time curve
- CYP
- cytochrome P450
- The American Society for Pharmacology and Experimental Therapeutics
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