Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K₁

The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K₁ through a drug interaction study with ketoconazole, a CYP4F2 inhibitor, and a pharmacogenetic study with CYP4F2*3. Twenty-one participants with different CYP4F2*3 polymorphisms were enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3). All participants were treated twice daily for 5 days with 200 mg of ketoconazole or placebo. Finally, a single dose of 10 mg vitamin K₁ was administered, plasma levels of vitamin K₁ were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K₁ and increased the average area under the concentration-time curve (AUC_inf) and peak concentration by 41% and 40%, respectively. CYP4F2*3 polymorphism also affected plasma levels of vitamin K₁ and its pharmacokinetics in a gene dose–dependent manner. The average AUC_inf value was 659.8 ng·h/mL for CYP4F2*1/*1, 878.1 ng·h/mL for CYP4F2*1/*3, and 1125.2 ng·h/mL for CYP4F2*3/*3 (P =.010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K₁ in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K₁ exposure due to CYP4F2-related drug interactions and genetic polymorphisms.