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目的研究CYP2C9-1075A>C及VKORC1-1639G>A基因多态性在服用华法林汉族人群中分布特性及其与药动学-药效学相关性。方法 PCR-SSP法及基因测序技术检测CYP2C9-1075A>C及VKORC1-1639G>A基因型,UPLC-MS测定血药浓度,以国际标准化比值评价药效学。结果 313例服用华法林患者中检测到CYP2C9*3 AC 34例,CYP2C9*2AC 1例,基因突变率分别为10.86%和0.32%。CYP2C9*2和CYP2C9*3等位基因频率分别为2.86%和97.14%。VKORC1-1639 G>A AA 261例,GA 51例,基因突变率分别83.39%和16.29%。313例服用华法林患者血药浓度为(0.51±0.18)(0.21~2.51)mg·L~(-1),国际标准化比值为1.63±0.60(0.91~3.62)。基因多态性与药动学-药效学相关性研究为未显示具有统计学意义的差异。结论研究汉族人群CYP2C9-1075A>C及VKORC1-1639G>A基因多态性的分布特点,对制订安全有效的华法林给药方案具有重要的临床意义。
Objective To investigate the distribution of CYP2C9-1075A> C and VKORC1-1639G> A polymorphisms in warfarin-donated Han population and its relationship with pharmacokinetics-pharmacodynamics. Methods CYP2C9-1075A> C and VKORC1-1639G> A genotypes were detected by PCR-SSP and gene sequencing. Plasma concentrations were determined by UPLC-MS. Pharmacodynamics were evaluated by international normalized ratio. Results CYP2C9 * 3 AC 34 cases, CYP2C9 * 2AC 1 case 313 cases were detected in warfarin patients, the gene mutation rates were 10.86% and 0.32% respectively. The CYP2C9 * 2 and CYP2C9 * 3 allele frequencies were 2.86% and 97.14%, respectively. VKORC1-1639G> A AA 261 cases, GA 51 cases, the gene mutation rates were 83.39% and 16.29%. The plasma concentration of 313 patients taking warfarin was (0.51 ± 0.18) (0.21-2.51) mg · L -1, and the international standardization ratio was 1.63 ± 0.60 (0.91 ~ 3.62). Genetic polymorphisms and pharmacokinetic-pharmacodynamic correlation studies did not show statistically significant differences. Conclusion The distribution of CYP2C9-1075A> C and VKORC1-1639G> A polymorphisms in Han population is of great clinical significance for the development of a safe and effective warfarin dosage regimen.