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 substant ial, suggesting that warfarin may be a potential CYP2C9 phenotyping probe. It is, however, limited by its ability to elevate the international normali zed 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 pro be. The objective of this study was to investigate the pharmacokinetics and pharmacodynamics of S- and B-warfarin in plasma following the administrati on of warfarin alone versus warfarin and vitamin K in CYP2C9 XI homozygotes . Healthy adults received, in a randomized crossover fashion in a fasted st ate, warfarin 10 mg orally or warfarin 10 mg plus vitamin K 10 mg orally. B lood samples were obtained over 5 days during each phase. INR measurements were obtained at baseline and day 2 in each phase. INR, AUC(0-infinity), an d t(1/2) of plasma S- and R-warfarin were examined. Eleven CYP2C9*1 homozyg otes (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 wa s not significantly different from warfarin with vitamin K. t(1/2) and AUC( 0-infinity) of both enantiomers did not significantly differ between the ph ases. It was concluded that INR is apparently attenuated by concomitant adm inistration of a single dose of vitamin K without affecting the pharmacokin etics 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 or al vitamin K.