CYP3A4基因多态性对阿立哌唑血药浓度及精神分裂症临床疗效的影响

Influence of CYP3A4 gene polymorphisms on blood concentration and therapeutic effects of aripiprazole in treatment of schizophrenia

目的研究细胞色素P450酶CYP3A4*4和CYP3A4*18B基因多态性对阿立哌唑血药浓度及临床疗效的影响,探讨阿立哌唑在不同个体间代谢差异的遗传背景。方法符合诊断标准的84例精神分裂症患者接受阿立哌唑(10～30 mg.d-1)为期4周的治疗,应用聚合酶链反应-限制性片断长度多态性方法(PCR-RFLP)检测84例患者CYP3A4*4和CYP3A4*18B基因多态性,采用反相高效液相色谱法测定阿立哌唑的谷血药浓度,并在治疗第0、2、4周分别进行阳性与阴性症状量表(PANSS)评分。结果在考察的84例患者中,CYP3A4*4未见突变;CYP3A4*18B基因*1/*1型有46例(55%),*1/*18B型34例(40%),*18B/*18B型4例(5%)。CYP3A4*18B基因型可影响血药浓度/剂量比,*1/*1型的血药浓度/剂量比最高,*1/*18B型次之,*18B/*18B型最低,*1/*1型与*18B/*18B型患者之间有显著差异(P<0.05),其余各组间未见显著差异(P>0.05)。不同基因型之间治疗2周和4周的临床疗效均未见显著差异(P>0.05)。结论 CYP3A4*18B基因多态性可影响阿立哌唑的血药浓度,但并不能确定与阿立哌唑的临床疗效有关。

AIM To explore the potential influence of cytochrome P450 CYP3A4＊4 and CYP3A4＊18B gene polymorphisms on the blood concentration and therapeutic effects of aripiprazole in treatment of schizophrenia, and to detect the genetic background of interindividual variations for aripiprazole metabolism.METHODS Eight-four patients with schizophrenia received aripiprazole l0 - 30 rag d-1for 4 weeks. The gene polymorphism of CYP3A4＊4 and CYP3A4＊18B were detected with PCR- RFLP, trough concentration of aripiprazole was measured by reversed phase high- performance liquid chromatography （RP-HPLC） , and the therapeutic effect of aripiprazole was evaluated with PANSS after 0, 2, 4 weeks treatment. RESULTS In the 84 schizophrenia patients, no mutation of CYP3A4＊4 was dectected. There were 46 patients with ＊1/＊1 genetype （55%）, 34 patients with ＊l/＊18B （40%）, and 4 patients with ＊18B/＊18B （5%） identified in CYP3A4＊18B. The concentration/dose ratios could be influenced by genotype of CYP3A4＊18B. The ratios of ＊1/＊1 genetype patients were the highest, those of ＊18B/＊18B were the lowest and those of ＊I/＊18B were moderate. The concentration/dose ratios of CYP3A 4 ＊ 1/＊ 1 were significantly higher than those of ＊ 18B/＊ 18B （P 〈 0.05 ） . There was no significantly difference between other two groups （P 〉 0.05） . There were no significantly difference in therapeutic effect among various CYP3A4＊18B genetypes after the treatment of aripiprazole for 2 and 4 weeks （P 〉 0.05） . CONCLUSION The gene polymorphisms of CYP3A4＊18B may be associated with the blood concentration of aripiprazole, but not confirmed with the therapeutic effect.