氯氮平在体内代谢与细胞色素P450 1A2-2964位点多态性的关系

Relationship between metabolism of clozapine in the body and polymorphisms of the locus cytochrome P450 1A2-2964

目的 :探讨氯氮平在精神分裂症患者体内代谢和细胞色素P4 5 0 1A2 2 964位点多态性关系 ,指导临床对不同患者合理使用氯氮平。方法 :采用固定剂量给药 ,用高效液相色谱法 (HPLC)测定血药浓度 ,用限制性片段长度多态性 (RFLPs)分析基因型。结果 :吸烟组和非吸烟组之间比较 ,吸烟组血浆氯氮平浓度低 ,去甲氯氮平 氯氮平比值高 (P <0 .0 5 ,P<0 .0 1)。P4 5 0 1A2 2 964位点等位基因G的频率为0 .75 ,A的频率为 0 .2 5。在非吸烟患者中 ,去甲氯氮平 氯氮平在w w基因型与非w w基因型 (w m +m m)之间无显著的统计学意义 (P >0 .0 5 )。在吸烟患者中 ,w w基因型去甲氯氮平 氯氮平要高于非w w基因型 (P <0 .0 5 )。在吸烟患者和非吸烟患者中w w基因型之间比较 ,吸烟患者的去甲氯氮平 氯氮平明显高于非吸烟患者 (P <0 .0 1) ;而非w w基因型之间无显著的统计学意义 (P >0 .0 5 )。结论 :吸烟能诱导P4 5 0 1A2的活性。P4 5 0 1A2 2 964位点等位基因均为G(w w)时诱导能力最强 ;发生G→A突变时 ,诱导能力降低。分析患者P4 5 0 1A2G 2 964A的多态性 。

AIM: To approach the relationship between the metabolism of clozapine in the body of patients with schizophrenia and polymorphisms of 2964 locus in cytochrome P450 1A2 (CYP1A2) for the reasonable use of clozapine. METHODS: A fixed dose administration was applied, HPLC was used for determining drug concentration in blood, and the restriction fragment length polymorphisms (RFLPs) was used for analyzing genotype of CYP1A2. RESULTS: Compared with non smoking group, the clozapine concentration in plasma of smoking group was lower, while the ratio of desmethylclozapine and clozapine was higher in smoking group (P< 0.05 and P< 0.01 , respectively). The frequency of the allele G in the locus 2964 of CYP1A2 was 0.75 , and the frequency of the allele A was 0.25 . There was no significant difference between w/w genotype and non w/w genotype(w/m+m/m) for desmethylclozapine/clozapine in non smoking patients (P> 0.05 ), but desmethylclozapine/clozapine of w/w genotype was higher than that of non w/w genotype in smoking patients(P< 0.05 ). Compared with w/w genotype of non smoking patients, desmethylclozapine/clozapine of w/w genotype of smoking patients was significantly higher (P< 0.01 ), but there was no significant difference for non w/w genotype (P> 0.05 ). CONCLUSION: Smoking can induce the activity of CYP1A2. The inducing ability of the allele locus of CYP1A2 2964 is stronger at both of G (w/w), and it decreased at G→A mutation. The polymorphism of CYP1A2 G 2964A is significant to the reasonable use of clozapine in the patients with schizophrenia.