STEADY-STATE CLEARANCE RATES OF WARFARIN AND ITS ENANTIOMERS IN THERAPEUTICALLY DOSED PATIENTS

Previous studies to identify the pharmacokinetics of R- and S-warfarin have not used steady-state area under the curve (AUG) data during the rapeutic doses of racemic warfarin. Instead they have used high single doses of either racemic warfarin or a single enantiomer in volunteers or have taken a single blood sample from anticoagulated patients and assumed full compliance and a steady-state status. In this study, a se ries of steady-state racemic warfarin, R-warfarin, and S-warfarin seru m concentrations, during a 24 h dosage interval, was measured in 10 co mpliant patients (5 females and 5 males) taking racemic warfarin. The anticoagulation status of all 10 patients according to the Internation al Normalised Ratio (INR) was stable. Their mean (SD) age and weight w ere 67.0 (9.9) yr and 63.9 (15.4) kg. The mean (SD) clearances derived from steady-state AUC values, following therapeutic dosing, for racem ic warfarin, R-warfarin, and S-warfarin were 2.40 (0.82), 2.30 (0.65), and 2.80 (1.17) ml/h/kg, respectively. The mean (SD) ratio of S:R-war farin clearance was 1.24 (0.40). Comparison of the clearance measured hom the AUG, of these patients, to one point determinations assuming s teady state for the samples drawn at either 6, 15, or 20 h after dosag e (during the dosing interval) showed some statistical differences. Mo st single point determinations of warfarin clearance assume that a sam ple 12 h postdose is equivalent to that of the steady-state concentrat ion, but in this study the steady-state concentration of only 6 patien ts occurred between 6 and 15 h postdose. This could explain why these studies demonstrate differences in the clearance of R- and S-warfarin compared to the values we have derived from steady-state AUC data usin g patients with proven compliance and therapeutic doses. (C) 1997 Wile y-Liss, Inc.