CYP3A4基因多态性对精神分裂症患者齐拉西酮血药浓度的影响

Influence of CYP3A4 Gene Polymorphisms on Plasma Drug Concentration of Ziprasidone in Schizophrenia Patients

目的研究细胞色素P450酶3A4(CYP3A4)基因多态性对精神分裂症患者齐拉西酮血药浓度的影响。方法纳入70例精神分裂症患者使用齐拉西酮治疗,采用聚合酶链反应-限制性内切片段长度多态性法(PCR-RFLP)进行CYP3A4基因分型测定,高效液相色谱串联质谱法(LC-MS/MS)测定齐拉西酮稳态谷浓度,单因素方差分析比较不同基因型组间血药浓度的差异,多元线性回归分析各协变量如性别、年龄、体重、剂量、合并用药、基因分型与齐拉西酮血药浓度的关系。结果70例患者中,男性组与女性组、<30岁组与≥30岁组、单一用药组与合并用药组间齐拉西酮血药浓度和浓度剂量比(C/D)无显著差异(P>0.05);CYP3A4*1G和*18B等位基因突变频率为25.71%和1.43%,*18B AA组与AG组、*1G CC组与CT组,CC组与TT组间血药浓度和C/D无显著差异(P>0.05),*1G TT组齐拉西酮C/D较CT组高,分别为(2.44±1.02)ng·mL^(-1)·mg^(-1)·d和(1.12±0.69)ng·mL^(-1)·mg^(-1)·d(P<0.05);多元线性回归分析调整后R2=0.503(P<0.001),剂量与血药浓度存在显著正相关,CYP3A4*1G TT型患者的血药浓度较CC型患者高35.40%(P<0.05)。结论CYP3A4基因多态性可影响齐拉西酮血药浓度,结合基因多态性和血药浓度能更好的实现个体化用药。

Objective To study the effect of cytochrome P450 enzyme 3A4(CYP3A4)gene polymorphism on the blood concentration of ziprasidone in patients with schizophrenia.Methods 70 schizophrenia patients received treatment of ziprasidone,and the CYP3A4(rs2242480,rs28371759)gene polymorphism were detected with PCR-RFLP.The steady-state plasma concentration of ziprasidone was detected by HPLC-MS/MS.The differences between the groups were tested by using single factor analysis of variance,and multiple linear regression was used to analyze the effects of sex,age,body weight,dosage,drug combination and gene polymorphism on plasma drug concentration.Results Among 70 patients,there was no significant difference in the corrected concentration-dose ratio(C/D)of ziprasidone between male group and female group,<30 age group and≥30 age group,single drug group and combination group,respectively(P>0.05).The gene frequencies of*1G and*18B were 25.71%and 1.43%respectively.The C/D of ziprasidone in patients with CYP3A4*1G TT genotype group was significantly higher than that with CYP3A4*1G CT group,which were(2.44±1.02)ng·mL^(-1)·mg^(-1)·d和(1.12±0.69)ng·mL^(-1)·mg^(-1)·d respectively(P<0.05).Multiple linear regression showed that after the adjustment of R2=0.503(P<0.001),there was a significant positive correlation between dosage and plasma drug concentration(P<0.01).The plasma drug concentration of CYP3A4*1G TT group was 35.40%higher than that of CC group(P<0.05).Conclusion CYP3A4 gene polymorphism can affect the blood concentration of ziprasidone.Combining gene polymorphism and blood concentration monitoring can better realize individualized medication.