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Rapid CommunicationShort Communication

Application of a First-Pass Effect Model to Characterize the Pharmacokinetic Disposition of Venlafaxine after Oral Administration to Human Subjects

David R. Taft, Ganesh R. Iyer, Leon Behar and Robert V. Digregorio
Drug Metabolism and Disposition October 1997, 25 (10) 1215-1218;
David R. Taft
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Ganesh R. Iyer
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Leon Behar
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Robert V. Digregorio
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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

  • Send reprint requests to: Dr. David R. Taft, Division of Pharmaceutics and Industrial Pharmacy, Long Island University, 1 University Plaza, Brooklyn, NY 11201.

  • Received March 5, 1997; accepted June 11, 1997.

  • ↵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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Drug Metabolism and Disposition
Vol. 25, Issue 10
1 Oct 1997
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Rapid CommunicationShort Communication

Application of a First-Pass Effect Model to Characterize the Pharmacokinetic Disposition of Venlafaxine after Oral Administration to Human Subjects

David R. Taft, Ganesh R. Iyer, Leon Behar and Robert V. Digregorio
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1215-1218;

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Rapid CommunicationShort Communication

Application of a First-Pass Effect Model to Characterize the Pharmacokinetic Disposition of Venlafaxine after Oral Administration to Human Subjects

David R. Taft, Ganesh R. Iyer, Leon Behar and Robert V. Digregorio
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1215-1218;
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