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华法林敏感性与CYP2C9、CYP3A5、ABCB1(MDR1)及其他因素相关。

Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.

作者信息

Wadelius M, Sörlin K, Wallerman O, Karlsson J, Yue Q-Y, Magnusson P K E, Wadelius C, Melhus H

机构信息

Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden.

出版信息

Pharmacogenomics J. 2004;4(1):40-8. doi: 10.1038/sj.tpj.6500220.

Abstract

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

摘要

口服抗凝剂华法林所需剂量差异很大,用药过量常导致出血。华法林由细胞色素P450酶CYP2C9、CYP1A2和CYP3A代谢。华法林的靶细胞水平可能取决于由三磷酸腺苷结合盒基因ABCB1(多药耐药基因1)编码的外排泵P-糖蛋白。采用固相微测序、焦磷酸测序和SNaPshot技术,对201例接受华法林治疗的稳定患者的CYP2C9、CYP3A5和ABCB1基因多态性进行了分析。CYP2C9基因变异、年龄、体重、同时进行的药物治疗以及治疗指征对这些患者的华法林剂量有显著影响,可解释剂量变异的29%。CYP3A5不影响华法林剂量。在低剂量患者中,含有外显子26 3435T变异的ABCB1单倍型出现频率过高。36例有严重出血并发症的患者的凝血酶原时间国际标准化比值高于189例无严重出血的华法林治疗患者,但CYP2C9、CYP3A5或ABCB1基因及等位基因变异无显著差异。

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