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.
Kim
J S
JS
Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York, USA.
Nafziger
A N
AN
Gaedigk
A
A
Dickmann
L J
LJ
Rettie
A E
AE
Bertino
J S
JS
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014812:Vitamin K / Q000008:administration & dosage / Q000494:pharmacology*; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D014812:Vitamin K; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase