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

Abstract

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 (AUCinf) 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 AUCinf 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.

Utility of Cytochrome P450 4F2 Genotyping to Assess Drug Interaction Risk for Brincidovovir, a Cytochrome P450 4F2 Substrate

“…The rs2108622 SNP of CYP4F2 evaluated in the current study has been shown to have 50%‐75% lower in vitro activity to metabolize vitamin K 13 . The clinical effect of this CYP4F2 SNP variant has recently been confirmed, with C/T and T/T individuals exhibiting increased circulating concentrations of vitamin K of 33% and 170%, respectively, following exogenous administration of vitamin K 14 . The reduced metabolism of vitamin K (a warfarin antagonist) in individuals with these SNPs is one of several factors leading to a higher dose requirement for warfarin 15 …”

“…The rs2108622 SNP of CYP4F2 evaluated in the current study has been shown to have 50%-75% lower in vitro activity to metabolize vitamin K. 13 The clinical effect of this CYP4F2 SNP variant has recently been confirmed, with C/T and T/T individuals exhibiting increased circulating concentrations of vitamin K of 33% and 170%, respectively, following exogenous administration of vitamin K. 14 The reduced metabolism of vitamin K (a warfarin antagonist) in individuals with these SNPs is one of several factors leading to a higher dose requirement for warfarin. 15 In contrast to the 170% increase in vitamin K concentrations, 14 subjects with the T/T genotype (lowest activity) in this meta-analysis of genotyping data from subjects administered brincidofovir across 6 phase 1 studies (Table S1) showed a relatively modest increase in brincidofovir exposure (up to 36%). The modest effect of the T genotype on brincidofovir exposure is likely due to the dual pathways for brincidofovir elimination (∼40% oxidation and ∼40% hydrolysis 20 ).…”

“…Due to the evolving understanding of how drugs interact with CYP4F2, clinical inhibitors of CYP4F2 have not been well‐established. Ketoconazole has been used as a clinical inhibitor of CYP4F2 in the past 8 and continues to have some clinical use as a CYP4F2 inhibitor in healthy subjects outside the United States 14 ; however, due to hepatic safety concerns raised by the FDA, the use of ketoconazole as a CYP inhibitor in healthy subjects has been curtailed in the United States. Sesamin, a major lignan in sesame seeds, has also been noted to inhibit the CYP4F2‐mediated metabolism of α and γ tocopherol (the tocopherols that comprise vitamin E) 24,25 ; however, the dose of this food product needed to fully inhibit CYP4F2 has not been established.…”

“…The heterozygous C/T variant is associated with approximately 50% reduced enzymatic activity, and the homozygous T/T variant is associated with approximately 75% reduced enzymatic activity in vitro, as compared to the C/C wild type 13 . The clinical effect of the T variant (C/T and T/T genotypes) on the clearance of vitamin K1 14 resulting in an increase in warfarin dose has been reported 15 . The clinical impact of these reduced activity CYP4F2 SNP variants was used as a surrogate to evaluate the potential effect of an inhibitor.…”

Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects

“…It is reported that most CYP enzymes exhibit marked genetic polymorphism, including copy number variation, missense mutation, insertion, deletion, and most of these genetic variations can affect the protein expression level or drug metabolic activity of enzyme. Clinical evidence has confirmed the apparent correlation between genetic polymorphisms of CYP and adverse drug reactions (ADRs), especially for drugs with narrow therapeutic windows (5)(6)(7).…”