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.
Original language | English |
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Pages (from-to) | 1453-1461 |
Number of pages | 9 |
Journal | Journal of Clinical Pharmacology |
Volume | 59 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2019 Nov 1 |
Bibliographical note
Funding Information:This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology, Korea. There are no competing interests to declare. Kyoung-Ah Kim and Ji-Young Park designed the research, wrote the manuscript, and analyzed the data. Jin-Woo Park wrote the manuscript and analyzed the data. If interested in our data, please contact Jin-Woo Park ([email protected]) or Ji-Young Park ([email protected]).
Publisher Copyright:
© 2019, The American College of Clinical Pharmacology
Keywords
- CYP4F2
- CYP4F2*3 polymorphism
- Vitamin K
- pharmacogenetics
- warfarin
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)