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Type: Journal article
Title: The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype
Author: Maddison, J.
Somogyi, A.
Jensen, B.
James, H.
Gentgall, M.
Rolan, P.
Citation: British Journal of Clinical Pharmacology, 2013; 75(1):208-216
Publisher: Blackwell Publishing Ltd
Issue Date: 2013
ISSN: 0306-5251
Statement of
John Maddison, Andrew A. Somogyi, Berit P. Jensen, Heather M. James, Melanie Gentgall and Paul E. Rolan
Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS: Using unequivocally pure (R)- and (S)-warfarin we have demonstrated that (R)-warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin. The extent of the interaction is dependent on VKORC1 genotype. AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUCPT((R)-warfarin) : AUCPT((S)-warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.
Keywords: Pharmacodynamics
Rights: © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
DOI: 10.1111/j.1365-2125.2012.04335.x
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Pharmacology publications

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