DISPOSITION OF WARFARIN ENANTIOMERS AND METABOLITES IN PATIENTS DURING MULTIPLE DOSING WITH RAC-WARFARIN

1 The disposition of warfarin enantiomers and metabolites has been stu died in 36 patients receiving chronic rac-warfarin therapy, titrated t o approximately the same anticoagulant response. 2 A stereoselective h .p.l.c. assay was employed to determine the concentrations of (R)- and (S)-warfarin, (R,S)-warfarin alcohol and (S)-7-hydroxywarfarin in pla sma and 24 h urine samples. The concentrations of (R)-7-hydroxywarfari n, (S,S)-warfarin alcohol and (R)-6- and (S)-6-hydroxywarfarin were al so determined in urine samples. The fractions unbound of warfarin enan tiomers were determined using equilibrium dialysis. 3 Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5-12 m g), in plasma concentrations of (S)-warfarin (0.48 mg 1(-1); 0.11-1.02 mg 1(-1)), (R)-warfarin (0.87 mg 1(-1); 0.29-1.82 mg 1(-1)), (R,S)-wa rfarin alcohol (0.31 mg 1(-1); 0.02-0.72 mg 1(-1)) and (S)-7-hydroxywa rfarin (0.25 mg 1(-1); 0.07-0.37 mg 1(-1)) and the percentage unbound of (S)-warfarin (0.53%; 0.29%-0.82%) and (R)-warfarin (0.54%; 0.26%-0. 96%). 4 The mean plasma clearances of warfarin enantiomers were 7.5 1 day(-1) per 70 kg (2.5-22.1) for (S)-warfarin and 3.6 1 day(-1) per 70 kg (1.6-8.8) for (R)-warfarin. There was a significant correlation be tween the estimated formation clearance of (S)-7-hydroxywarfarin and t he clearance of (S)-warfarin, which accounted for much of the variabil ity in the latter. 5 The renal clearance of (S)-7-hydroxywarfarin (mea n 5.6 1 day(-1) per 70 kg; range 0.8-18.8) and (R,S)-warfarin alcohol (2.8 1 day(-1) per 70 kg; 0.1-16.7) was variable across the study grou p.