CYP1A2、CYP2D6和CYP2C19基因多态性与氯氮平及其代谢物血药浓度的相关性研究

目的：研究CYP1A2、CYP2D6和CYP2C19基因多态性与精神分裂症患者氯氮平（clozapine，CLZ）及其活性代谢物去甲氯氮平（N-desmethy clozapine，N-CLZ）血药浓度的相关性。方法：纳入156例经CLZ单药治疗1个月以上的精神分裂症患者，采集清晨服药前空腹血，采用液相色谱-串联质谱（LC-MS/MS）法测定CLZ及N-CLZ稳态谷浓度。通过Axiom基因芯片分析技术检测CYP1A2（*1C、*1F）、CYP2D6（*2、*10）、CYP2C19（*2、*3）等6个SNP位点的基因型，比较不同基因型患者CLZ及其代谢物的浓度剂量比（C/D）及代谢物与CLZ血药浓度比值（C_N-CLZ/C_CLZ）的差异。结果：CYP2D6*10基因多态性与N-CLZ C/D具有相关性（P<0.01）。CYP1A2*1C、CYP2D6（*2、*10）基因多态性与C_N-CLZ/C_CLZ具有相关性（P<0.05，P<0.01，P<0.01）。CYP1A2*1F、CYP2C19*2、CYP2C19*3基因多态性与C/D及C_N-CLZ/C_CLZ无相关性（P>0.05）。结论：CYP1A2*1C和CYP2D6（*2、*10）基因多态性对CLZ代谢存在影响，建议临床在使用CLZ治疗前检测患者CYP1A2*1C和CYP2D6（*2、*10）基因型，为CLZ个体化治疗提供参考。

Associations of CYP1A2, CYP2D6 and CYP2C19 gene polymorphisms with clozapine and its serum metabolites

OBJECTIVE To explore the associations of CYP1A2, CYP2D6 and CYP2C19 gene polymorphisms with clozapine and its active metabolite norclozapine in schizophrenics.METHODS Fasting blood samples were collected from 156 schizophrenics receiving clozapine for over 1 month.The steady valley concentrations of clozapine and norclozapine were determined by LC-MS/MS.The genotypes of 6 SNP loci CYP1A2(*1C, *1F), CYP2D6(*2, *10) and CYP2C19(*2, *3) were detected by Axiom gene chip analysis.The differences of concentration/(dosage×body weight) ratio(C/D) and C_N-CLZ/C_CLZ were compared among all genotypic groups on clozapine.RESULTS CYP2D6*10 gene polymorphism was associated with C/D ratio of norclozapine(P<0.01).CYP1A2*1C gene polymorphism was associated with C_N-CLZ/C_CLZ(P<0.05).And CYP2D6*2 and CYP2D6*10 gene polymorphisms were associated with C_N-CLZ/C_CLZ(P<0.01).No association existed between CYP1A2*1F, CYP2C19*2, CYP2C19*3 gene polymorphisms and C/D and C_N-CLZ/C_CLZ.After eliminating the influence of CYP2D6*2, there was a correlation between CYP1A2*1C gene polymorphism and C_N-CLZ/C_CLZ(P<0.01);After eliminating the influence of CYP2D6*10, a correlation between CYP1A2*1C gene polymorphism and C_N-CLZ/C_CLZ(P<0.05);After eliminating the influence of CYP1A2*1C, a correlation between CYP2D6*2 gene polymorphism and C_N-CLZ/C_CLZ(P<0.01).CYP2D6*10 gene polymorphism was associated with C_N-CLZ/C_CLZ(P<0.01).CONCLUSION CYP1A2*1C and CYP2D6(*2, *10) gene polymorphisms exert some effect on clozapine metabolism.It is suggested that CYP1A2*1C and CYP2D6(*2, *10) genotypes in patients with clozapine should be detected before clozapine treatment to provide rationales for its individual treatment.