基于细胞色素P450基因多态性的文拉法辛药代动力学和安全性评价

Evaluation of pharmacokinetics and safety of venlafaxine based on cytochrome P450 gene polymorphism

目的对CYP450基因多态性与文拉法辛药代动力学和安全性的相关性进行系统评价。方法使用关键词在Pub Med,Cochrane Library,Web of Science,中国知网,万方数据库,维普数据库上进行文献检索,检索时间均为从建库至2019-04-06,获取有关基因多态性对文拉法辛药代动力学或安全性影响的文献。由2名研究者独立阅读文献,严格按照入排标准筛选文献。结果 CYP2D6*10(rs1065852)不同基因型CC、CT、TT之间的CODV/CVEN和血药浓度差异均有统计学意义(均P<0.05);对CYP2D6*1、*2、*2A、*3、*4、*5、*6、*7、*8、*9、*10、*11、*12和*17等位基因进行赋值,表征酶活性,进行相关性分析,结果与文拉法辛血药浓度呈负相关(P<0.05);CYP2C19*2和*3可能会影响文拉法辛体内药代动力学过程,使酶活性降低;CYP1A2的rs2470890位点等位基因及基因型在有效组和无效组之间的差异有统计学意义(等位基因:P<0.01;基因型:P<0.05)。结论 CYP2D6(*1、*2、*2A、*3、*4、*5、*6、*7、*8、*9、*10、*11、*12、*17、*29、*41)、CYP2C19(*1、*2、*3)、CYP2C9(*1、*2)和CYP1A2(rs2470890)基因多态性可影响文拉法辛代谢;CYP2D6慢代谢者发生药物不良反应的风险更高,建议使用文拉法辛前,充分考虑CYP450基因多态性的影响,确保临床用药安全。

Objective The association between the cytochrome P450(CYP450)gene polymorphism and pharmacokinetics as well as safety was evaluated systematically.Methods Literature search was performed on PubMed,Cochrane Library,Web of Science,China Knowledge Network,Wanfang Database,and Weipu Database,from the time of establishment of respective library to April 6,2019,with keywords relevant with gene polymorphisms,pharmacokinetics and safety.Each literature was reviewed independently by two investigators and was screened in strict accordance with the inclusion and exclusion criteria.Results There were significant differences in CODV/CVENand plasma concentrations between different genotypes of CC,CT and TT in CYP2 D6~*10(rs1065852)(P<0.05).By assigning and characterizing the enzyme activity of CYP2 D6~*1,~*2,~*2 A,~*3,~*4,~*5,~*6,~*7,~*8,~*9,~*10,~*11,~*12,and~*17 alleles,the enzyme activity was negatively correlated with venlafaxine plasma concentration(P<0.05).CYP2 C19~*2 and~*3 may affect the pharmacokinetics of venlafaxine and reduce the enzyme activity.The rs2470890 allele of CYP1 A2 were statistically significant between the effective and ineffective groups(allele:P<0.01;genotype:P<0.05).Cconclusion The gene polymorphisms of CYP2 D6(~*1,~*2,~*2 A,~*3,~*4,~*5,~*6,~*7,~*8,~*9,~*10,~*11,~*12,~*17,~*29,~*41),CYP2 C19(~*1,~*2,~*3),CYP2 C9(~*1,~*2)and CYP1 A2(rs2470890)can affect the metabolism of venlafaxine;CYP2 D6 slow metabolizers have a higher risk of adverse effects when using venlafaxine.To ensure the safety,it is recommended to detect CYP450 enzyme gene polymorphisms before using venlafaxine.