DOSE-DEPENDENT PHARMACOKINETICS OF WARFARIN IN HEALTHY-VOLUNTEERS

Purpose. To examine the pharmacokinetics of warfarin after administrat ion of single oral doses (2, 5, and 10 mg) to healthy male volunteers. Methods. A sensitive reverse-phase HPLC method was used to quantify w arfarin plasma concentrations as low as 6 ng/ml. Blood samples were co llected for up to 120 hours following administration of these doses. R esults. As the dose decreased from 5 to 2 mg, the apparent volume of d istribution (V/F) increased from 12 to 21 liters and the terminal half -life (t(1/2)) increased from 47 to 71 hours, Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t(1/2) and V/F may be due to saturable tissue bi nding of this drug. It appears that a previously undetected and prolon ged terminal phase may exist but can not be adequately characterized w ith the 120-hour sampling interval. To evaluate this long t(1/2), a fo llow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase st arted to become apparent when plasma levels declined to less than 100 ng/ml. The t(1/2) of this terminal phase was determined to be approxim ately one week. Conclusions. This is the first report that documents t he dose-dependent pharmacokinetics of warfarin and the previously unre ported long t(1/2) of one week for warfarin in humans.