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Dose-Dependent Pharmacokinetics of Warfarin in Healthy Volunteers

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Abstract

Purpose. To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers.

Methods. A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses.

Results. As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t1/2 of this terminal phase was determined to be approximately one week.

Conclusions. This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t1/2 of one week for warfarin in humans.

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Authors
  1. Shang-Ying P. King
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  2. Mark A. Joslin
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  3. Karen Raudibaugh
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  4. Henry J. Pieniaszek Jr.
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  5. Irma H. Benedek
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King, SY.P., Joslin, M.A., Raudibaugh, K. et al. Dose-Dependent Pharmacokinetics of Warfarin in Healthy Volunteers. Pharm Res 12, 1874–1877 (1995). https://doi.org/10.1023/A:1016223418652

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  • DOI: https://doi.org/10.1023/A:1016223418652

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