Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S -Warfarin in Healthy Subjects
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ORIGINAL RESEARCH ARTICLE
Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects Chanan Shaul1,2 • Simcha Blotnick1 • Mordechai Muszkat1 • Meir Bialer2 Yoseph Caraco1
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Ó Springer International Publishing Switzerland 2016
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-hydroxywarfarin was 45, 65 and 75%, respectively (p \ 0.001). & Yoseph Caraco [email protected] 1
Clinical Pharmacology Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120 Jerusalem, Israel
2
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel
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.
Key Points The metabolism of S-warfarin is mediated predominantly by the activity of CYP2C9. Carriers of the CYP2C9*2 or CYP2C9*3 allelic variants have been shown to exhibit reduced S-warfarin clearance but the extent of reduction was not clearly defined. The findings in the present study indicate that the decrease in the oral clearance of S-warfarin is genotype specific. Thus, among carriers of CYP2C9*1/*2, CYP2C9*1/*3 and carriers of 2 variant alleles, the oral clearance of S-warfarin is reduced by 25, 39 and 47%, respectively. The formation clearance of 6 and 7 S-hydroxy-warfarin, 2 metabolites produced by CYP2C9, was reduced by 45, 65 and 75%, respecti
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