Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe.

Evidence for the selectivity of S-warfarin metabolism by CYP2C9 is substantial, suggesting that warfarin may be a potential CYP2C9 phenotyping probe. It is, however, limited by its ability to elevate the international normalized ratio (INR) and potentially cause bleeding. The effect of vitamin K to attenuate the elevation of INR may enable the safe use of warfarin as a probe. The objective of this study was to investigate the pharmacokinetics and pharmacodynamics of S- and R-warfarin in plasma following the administration of warfarin alone versus warfarin and vitamin K in CYP2C9*1 homozygotes. Healthy adults received, in a randomized crossover fashion in a fasted state, warfarin 10 mg orally or warfarin 10 mg plus vitamin K 10 mg orally. Blood samples were obtained over 5 days during each phase. INR measurements were obtained at baseline and day 2 in each phase. INR, AUC0-infinity, and t1/2 of plasma S- and R-warfarin were examined. Eleven CYP2C9*1 homozygotes (3 men, 8 women) were enrolled. INR at day 2 following warfarin 10 mg was 1.18 +/- 0.19, which differed significantly from baseline (INR = 1.00 +/- 0.05) and warfarin with vitamin K (INR = 1.06 +/- 0.07). INR at baseline was not significantly different from warfarin with vitamin K. t1/2 and AUC0-infinity of both enantiomers did not significantly differ between the phases. It was concluded that INR is apparently attenuated by concomitant administration of a single dose of vitamin K without affecting the pharmacokinetics of either warfarin stereoisomer. Warfarin 10 mg may be safely used as a CYP2C9 probe in *1 homozygotes when given concomitantly with 10 mg of oral vitamin K.

RCT Entities:   Population Interventions Outcomes