Pavani Addepalli, Naushad Shaik Mohammad, Stanley Balraj Alex, Kamakshi Renganathan Gnanambal, Abinaya Krishnan, Amaresh Rao Malempati, Uma Addepally, Kutala Vijay Kumar
Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India.
Pharmacogenomics. 2015;16(4):393-400. doi: 10.2217/pgs.14.185.
To evaluate the impact of CYP2C92 and CYP2C93 variants on binding and hydroxylation of warfarin.
MATERIALS & METHODS: Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based in silico models were developed for the genetic variants.
CYP2C92 and CYP2C93 variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores (in silico).
CYP2C92 and CYP2C93 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014.
评估CYP2C92和CYP2C93基因变异对华法林结合及羟基化的影响。
基于199例患者的数据建立了华法林药代动力学的多元线性回归模型。针对这些基因变异构建了基于Pymol的计算机模拟模型。
CYP2C92和CYP2C93基因变异表现出较高的华法林/7-羟基华法林水平（多元线性回归模型），与华法林的氢键呈剂量依赖性破坏，S-华法林C7与CYP2C9的Fe-O之间的距离呈剂量依赖性增加，计算机模拟的滑行评分呈剂量依赖性降低。
CYP2C92和CYP2C93基因变异导致与华法林的氢键相互作用破坏以及C7与Fe-O之间距离变长，从而由于华法林结合亲和力降低而损害华法林7-羟基化。原始稿件于2014年5月7日提交；修订稿件于2014年10月30日提交。
