CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响

刘亦伟，林翠鸿，王长连，蔡斌，柯蒙，黄品芳

中国药学杂志 ›› 2016, Vol. 51 ›› Issue (19) : 1682-1689.

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中国药学杂志
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中国药学杂志 ›› 2016, Vol. 51 ›› Issue (19) : 1682-1689. DOI: 10.11669/cpj.2016.19.013
论著

CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响

  • 刘亦伟a，林翠鸿a，王长连a，蔡斌b，柯蒙a，黄品芳a*
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The Effects of CYP3A4*18A,CYP3A4*18B and MDR1 C3435T Polymorphisms on Plasma Concentration and Efficacy of Atorvastatin

  • LIU Yi-weia, LIN Cui-honga, WANG Chang-liana, CAI Binb, KE Menga, HUANG Pin-fanga*
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摘要

目的 探讨高脂血症患者CYP3A4*18A、*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度、调脂疗效的影响。方法 115例福建籍汉族高脂血症患者以聚合酶链反应-限制性片段长度多态性法(polymerase chain reaction-restriction fragment length polymorphism，PCR-RFLP)进行基因分型，HPLC-UV检测阿托伐他汀稳态血药谷浓度，均相酶法监测治疗前、用药1个月后血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平。用SPSS13.0软件以ANOVA方差分析高脂血症患者基因型与调脂疗效、血药浓度之间的关系。结果 115例高脂血症患者，CYP3A4*18A、*18B的突变频率分别为3.48%和23.48%，MDR1 C3435T突变率为31.74%，三基因位点SNPs分布与文献报道的国人正常人群无显著性差异(P＞0.05);CYP3A4*18A和MDR1 C3435T各基因型患者ATV血药浓度组间及组内差异均无统计学意义(P＞0.05)。CYP3A4*18B基因突变纯合子(AA)组患者ATV血药浓度显著高于突变杂合子(GA)组和野生型纯合子(GG)组(P=0.016)。CYP3A4*18A、MDR1 C3435T不同基因型患者的调脂效率无显著性差异(P＞0.05)，CYP3A4*18B基因的AA组患者TC调脂效果显著优于GA组和GG组患者(P=0.02);LDL-C变化率三基因型组间均有显著差异，依次为AA组＞GA组＞GG组(P=0.01)，对TG和HDL-C的调节作用3种基因型患者无显著性差异(P＞0.05)。治疗前后，TC的变化率与血药浓度呈显著性相关(P=0.031)，而其余3种脂质变化率与血药浓度相关性无统计学意义(P＞0.05)。结论 MDR1 C3435T与CYP3A4*18A基因SNPs(single nucleotide polymorphisms)，不影响ATV血药浓度及其疗效。携带CYP3A4*18B基因的患者接受ATV治疗时，比未携带者血药浓度高，调脂疗效更显著。

Abstract

OBJECTIVE To investigate the interindividual variabilities of plasma concentration and lipid-regulating efficacy of atorvastatin in patients with hyperlipidemia through the genotyping of CYP3A4*18A, *18B and MDR1 C3435T genes.METHODS One hundred and fifteen Chinese Han population with hyperlipidemia were genotyped by the PCR-RFLP (restriction fragment length polymorphism).The steady-state plasma trough concentrations of atorvastatin were measured by high performance liquid chromatography (HPLC)-UV.The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were monitored by the homogeneous enzyme method before treatment and 1 month after medication.RESULTS The mutation frequencies of CYP3A4*18A,*18B and MDR1 C3435T were 3.48%,23.48% and 31.74% respectively.It shows no statistically significant difference for the SNPs frequencies between the normal population reported and patients selected.Patients with CYP3A4*18B homozygous mutant (AA) showed a significantly higher plasma concentration of ATV compared with the G/A heterozygous mutat patients or the G/G wild-type homozygous (P=0.016).However,no significant difference could be shown in the patients with CYP3A4*18A and MDR1 C3435T genotypes(P＞0.05).Neither CYP3A4*18A nor MDR1 C3435T could be shown a significant difference in the lipid lowering efficiency(P>0.05).Patients carrying the homozygous mutant (AA) of the CYP3A4*18B gene showed a significantly higher TC lipid-regulating effect compared with patients with the GA or GG genetic variant (P=0.02). The LDL-C change rates among the three genotype groups were significantly different, with AA group >GA group >GG group (P=0.01) and the regulation of TG and HDL-C for AA,GA or GG was compared without finding any significant difference (P>0.05).The TC changerates and plasma concentration were significantly correlated (P=0.031) before and after treatment,while there was no statistical significance in the correlation of the other three lipid change rates with plasma concentration (P＞0.05).CONCLUSION The SNPs MDR1 C3435T and CYP3A4*18A do not affect the plasma concentration and efficacy of ATV. In ATV therapy, patients with the CYP3A4*18B gene exhibit higher plasma concentrations than the non-carriers, and the lipid-lowering efficacy was more pronounced.

关键词

阿托伐他汀 / CYP3A4*18A / CYP3A4*18B / MDR1 C3435T / 基因多态性 / 血药浓度 / 聚合酶链反应-限制性片段长度多态性法

Key words

atorvastatin / CYP3A4*18A / CYP3A4*18B / MDR1C3435T / polymorphism / plasma concentration / PCR-RFLP

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刘亦伟，林翠鸿，王长连，蔡斌，柯蒙，黄品芳. CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响[J]. 中国药学杂志, 2016, 51(19): 1682-1689 https://doi.org/10.11669/cpj.2016.19.013
LIU Yi-wei, LIN Cui-hong, WANG Chang-lian, CAI Bin, KE Meng, HUANG Pin-fang. The Effects of CYP3A4*18A,CYP3A4*18B and MDR1 C3435T Polymorphisms on Plasma Concentration and Efficacy of Atorvastatin[J]. Chinese Pharmaceutical Journal, 2016, 51(19): 1682-1689 https://doi.org/10.11669/cpj.2016.19.013
中图分类号： R969.1   

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基金

国家自然科学基金资助项目(81171114);福建省教育厅科技项目(JA09107)
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