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目的 研究细胞色素P450酶和转运体的基因多态性对阿立哌唑药动学(PK)参数的影响。方法 共纳入33名健康受试者，单次口服阿立哌唑口崩片10 mg。采用液相色谱-串联质谱法测定阿立哌唑的血药浓度，并以Phoenix WinNonLin 8.2软件计算PK参数[半衰期(T1/2)、达峰时间(Tmax)、血浆峰浓度(Cmax)和药-时曲线下面积(AUC0-72 h)]。采用DNA测序技术检测细胞色素P450酶(CYP2D6、CYP3A4和CYP3A5)和转运体(ABCB1)共22个位点的单核苷酸多态性。采用多元线性回归模型法分析细胞色素P450酶和转运体基因多态性分布与阿立哌唑PK参数之间的相关性。结果 相比于CYP2D6(rs1135840)的CC基因型，其CG/GG基因型受试者的阿立哌唑T1/2显著延长；相比于CYP2D6(rs1065852)的GG基因型，其GA/AA基因型的T1/2显著延长，AUC0-72 h显著升高；相比于CYP2D6(rs28371725)的CC基因型，其CT基因型的Cmax显著降低。此外，与CYP2D6正常代谢型相比，CYP2D6中间代谢型的T1/2显著延长。多元线性回归分析表明，CYP3A4*4多态性和性别对阿立哌唑Tmax影响显著；CYP2D6代谢型和CYP3A5*3多态性对阿立哌唑T1/2影响显著；CYP2D6代谢型和性别对AUC0-72 h影响显著。结论 CYP3A4*4、CYP3A5*3和CYP2D6基因多态性对健康受试者阿立哌唑体内PK参数具有显著影响。
Abstract：AIM To analyze the correlation between genetic polymorphisms of cytochrome P450 enzymes and transporters and the pharmacokinetic(PK) parameters of aripiprazole. METHODS A total of 33 healthy volunteers were enrolled, and a single oral dose of 10 mg aripiprazole orally disintegrating tablet was administered. The blood concentrations of aripiprazole were quantified by liquid chromatography-tandem mass spectrometry. PK parameters [half-life(T1/2), time to peak(Tmax), peak plasma concentration(Cmax), and area under the drug-time curve(AUC0-72 h)] were calculated by Phoenix WinNonLin 8.2 software. DNA sequencing technology was employed to determine 22 single nucleotide polymorphisms in cytochrome P450 enzymes(CYP2D6, CYP3A4, and CYP3A5) and transporters(ABCB1). Multiple linear regression modeling was employed to analyze the correlations between the distributions of genetic polymorphisms in cytochrome P450 enzymes and transporter genes and the pharmacokinetic(PK) parameters of aripiprazole. RESULTS Compared to subjects with the CYP2D6(rs1135840) CC genotype, those with the CG/GG genotype had a significantly prolonged T1/2 of aripiprazole. Compared to subjects with the CYP2D6(rs1065852) GG genotype, those with the GA/AA genotype had a significantly prolonged T1/2 and a significantly elevated AUC0-72 h. And compared to subjects with the CYP2D6(rs28371725) CC genotype, those with the CT genotype had a significantly reduced Cmax. Additionally, the T1/2 of CYP2D6 intermediate metabolizers was significantly prolonged compared to that of extensive metabolizers. Multivariate linear regression analysis showed that the CYP3A4*4 polymorphism and gender significantly affected the Tmax of aripiprazole; the CYP2D6 metabolic phenotype and CYP3A5*3 polymorphism significantly affected the T1/2 of aripiprazole; and the CYP2D6 metabolic phenotype and gender significantly affected the AUC0-72 h. CONCLUSION The polymorphisms of CYP3A4*4, CYP3A5*3, and CYP2D6 genes significantly affect the PK parameters of aripiprazole in healthy subjects.
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基本信息:
DOI：10.19577/j.1007-4406.2025.12.001
中图分类号:R969.1
引用信息:
[1]叶丽冰,杨水新,姚冲,等.细胞色素P450酶和转运体的基因多态性对阿立哌唑药动学参数的影响[J].中国临床药学杂志,2025,34(12):881-888.DOI:10.19577/j.1007-4406.2025.12.001.
基金信息:
湖州市科技计划公益性应用研究项目（编号2021GZ71、2024GY16）; 湖州市中心医院青年英才项目（编号2020YC12）; 湖州市南太湖优秀卫生青年人才项目（编号rsk2023001）