Dose-dependent pharmacokinetics of warfarin in healthy volunteers

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

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.

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.

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.