Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Graduate Program in Genetic Counseling, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Clin Transl Sci. 2020 Sep;13(5):941-949. doi: 10.1111/cts.12781. Epub 2020 Apr 9.
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)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based on CYP2C9 and VKORC1 genotypes, 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.
华法林的精确剂量对于在没有不良反应的情况下达到治疗效果很重要。药物基因组学解释了华法林反应中一些个体间的差异，但在遗传因素的背景下，药物-药物相互作用的关注较少。我们回顾性研究了细胞色素 P450（CYP）2C9 和维生素 K 环氧化物还原酶复合物（VKORC）1 基因型与同时暴露于 CYP2C9 相互作用药物对长期华法林抗凝的联合影响。根据 CYP2C9 和 VKORC1 基因型预测对华法林敏感的研究参与者，其国际标准化比值（INR）随时间的变化具有显著更大的可变性。同时服用 CYP2C9 相互作用药物的参与者发现 INR 可变性更大，治疗范围的时间更少。INR 可变性与基因型的关联主要归因于未暴露于相互作用药物的亚组，而相互作用药物暴露的影响则归因于正常反应者亚组。我们的研究结果强调了在药物基因组学研究中考虑药物相互作用的重要性。
