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Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects

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Abstract

Background

Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions.

Objective

The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes.

Methods

Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period.

Results

Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CLS was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001).

Conclusions

The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision.

Trial registration: Clinicaltrials.gov Identifier NCT00162474.

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Authors and Affiliations

  1. Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel

    Chanan Shaul, Simcha Blotnick, Mordechai Muszkat & Yoseph Caraco

  2. Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Chanan Shaul & Meir Bialer

Authors
  1. Chanan Shaul
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  2. Simcha Blotnick
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  3. Mordechai Muszkat
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  4. Meir Bialer
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  5. Yoseph Caraco
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Corresponding author

Correspondence to Yoseph Caraco.

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Conflict of interest

Chanan Shaul declares no conflicts of interest. Simcha Blotnick declares no conflicts of interest. Mordechai Muszkat declares no conflicts of interest. Meir Bialer declares no conflicts of interest. Yoseph Caraco declares no conflicts of interest.

Funding

The corresponding author (YC) received a grant from the Bi-National US-Israeli Science Foundation (BSF) (Grant # 2003229).

Approval by the ethic committee and informed consent

The study protocol was approved by the Hadassah Institutional Review Board and following a detailed explanation all subjects signed an informed consent (Approval number: Warfarin PK, 8-19.12.03).

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Shaul, C., Blotnick, S., Muszkat, M. et al. Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects. Mol Diagn Ther 21, 75–83 (2017). https://doi.org/10.1007/s40291-016-0247-7

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  • DOI: https://doi.org/10.1007/s40291-016-0247-7

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