Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K-1
- Authors
- Park, Jin-Woo; Kim, Kyoung-Ah; Park, Ji-Young
- Issue Date
- 11월-2019
- Publisher
- WILEY
- Keywords
- Vitamin K-1; warfarin; pharmacogenetics
- Citation
- JOURNAL OF CLINICAL PHARMACOLOGY, v.59, no.11, pp.1453 - 1461
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CLINICAL PHARMACOLOGY
- Volume
- 59
- Number
- 11
- Start Page
- 1453
- End Page
- 1461
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/62109
- DOI
- 10.1002/jcph.1444
- ISSN
- 0091-2700
- Abstract
- The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K-1 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 K-1 was administered, plasma levels of vitamin K-1 were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K-1 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 K-1 and its pharmacokinetics in a gene dose-dependent manner. The average AUC(inf) value was 659.8 ng center dot h/mL for CYP4F2*1/*1, 878.1 ng center dot h/mL for CYP4F2*1/*3, and 1125.2 ng center dot h/mL for CYP4F2*3/*3 (P = .010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K-1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K-1 exposure due to CYP4F2-related drug interactions and genetic polymorphisms.
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Collections - College of Medicine > Department of Medical Science > 1. Journal Articles
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