The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype
Article first published online: 14 DEC 2012
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 1, pages 208–216, January 2013
How to Cite
Maddison, J., Somogyi, A. A., Jensen, B. P., James, H. M., Gentgall, M. and Rolan, P. E. (2013), The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype. British Journal of Clinical Pharmacology, 75: 208–216. doi: 10.1111/j.1365-2125.2012.04335.x
- Issue published online: 14 DEC 2012
- Article first published online: 14 DEC 2012
- Accepted manuscript online: 22 MAY 2012 11:39PM EST
- Received; 4 March 2012; Accepted; 12 March 2012; Accepted Article Published Online; 23 May 2012
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.