Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac‐warfarin [see comments]

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Abstract
1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac‐warfarin therapy, titrated to 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 plasma and 24 h urine samples. The concentrations of (R)‐7‐ hydroxywarfarin, (S,S)‐warfarin alcohol and (R)‐6‐ and (S)‐6‐ hydroxywarfarin were also determined in urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5‐12 mg), in plasma concentrations of (S)‐ warfarin (0.48 mg l(‐1); 0.11‐1.02 mg l(‐1)), (R)‐warfarin (0.87 mg l(‐ 1); 0.29‐1.82 mg l(‐1)), (R,S)‐warfarin alcohol (0.31 mg l(‐1); 0.02‐ 0.72 mg l(‐1)) and (S)‐7‐hydroxywarfarin (0.25 mg l(‐1); 0.07‐0.37 mg l(‐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 between the estimated formation clearance of (S)‐7‐hydroxywarfarin and the clearance of (S)‐warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)