Impact of CYP2C9-Interacting Drugs on Warfarin Pharmacogenomics

被引：19

作者：

Agrawal, Saaket ^{[1
]}

Heiss, Meredith S. ^{[2
]}

Fenter, Remington B. ^{[2
]}

Abramova, Tatiana, V ^{[1
]}

Perera, Minoli A. ^{[1
,3
,4
]}

Pacheco, Jennifer A. ^{[4
]}

Smith, Maureen E. ^{[4
,5
]}

Rasmussen-Torvik, Laura J. ^{[6
]}

George, Alfred L., Jr. ^{[1
,3
,4
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USA

[2] Northwestern Univ, Feinberg Sch Med, Grad Program Genet Counseling, Chicago, IL 60611 USA

[3] Northwestern Univ, Feinberg Sch Med, Ctr Pharmacogen, Chicago, IL 60611 USA

[4] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA

[5] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA

[6] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

来源：

CTS-CLINICAL AND TRANSLATIONAL SCIENCE | 2020年 / 13卷 / 05期

基金：

美国国家卫生研究院;

关键词：

GENETIC-VARIANTS; CYP2C9; VARIABILITY; INHIBITION; PREDICT; VKORC1;

D O I：

10.1111/cts.12781

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug-drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9and vitamin K epoxide reductase complex (VKORC)1genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based onCYP2C9andVKORC1genotypes, had significantly greater international normalized ratio (INR) variability over time. Participants who were concurrently taking CYP2C9-interacting drugs were found to have greater INR variability and lesser time in therapeutic range. The associations of INR variability with genotype were driven by the subgroup not exposed to interacting drugs, whereas the effect of interacting drug exposure was driven by the subgroup categorized as normal responders. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies.

引用

页码：941 / 949

页数：9

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