Mechanistic insights into the effect of CYP2C9*2 and CYP2C9*3 variants on the 7-hydroxylation of warfarin

被引：0
作者：
Pavani, Addepalli [1 ]
Naushad, Shaik Mohammad [2 ]
Stanley, Balraj Alex [2 ]
Kamakshi, Renganathan Gnanambal [2 ]
Abinaya, Krishnan [2 ]
Rao, Malempati Amaresh [3 ]
Uma, Addepally [4 ]
Kutala, Vijay Kumar [1 ]
机构：
[1] Nizams Inst Med Sci, Dept Clin Pharmacol & Therapeut, Hyderabad, Andhra Pradesh, India
[2] SASTRA Univ, Sch Chem & Biotechnol, Tirumalaisamudram, Thanjavur, India
[3] Nizams Inst Med Sci, Cardiothorac Surg, Hyderabad, Andhra Pradesh, India
[4] Jawaharlal Nehru Technol Univ, Ctr Biotechnol, Hyderabad, Andhra Pradesh, India
来源：
PHARMACOGENOMICS | 2015年 / 16卷 / 04期
关键词：
7-hydroxy warfarin; CYP2C9*2; CYP2C9*3; multiple linear regression; warfarin; HUMAN CYTOCHROME-P450 2C9; POLYMORPHIC VARIANTS; CATALYTIC-ACTIVITY; JAPANESE PATIENTS; CLINICAL FACTORS; CYP2C9; METABOLISM; POPULATION; ANTICOAGULATION; ASSOCIATION;
D O I：
10.2217/PGS.14.185
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
Aim: To evaluate the impact of CYP2C9*2 and CYP2C9*3 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. Results: CYP2C9*2 and CYP2C9*3 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). Conclusion: CYP2C9*2 and CYP2C9*3 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.
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收藏
页码：393 / 400
页数：8
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