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他汀类药物抑制胆固醇合成途径的限速酶3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMG-CoA还原酶)的活性,抑制胆固醇的生成,上调肝细胞表面的LDL受体以加快LDL的分解代谢。阿托伐他汀以活性酸形式给药,通过被动扩散或OATP1B1转运进入肝细胞,主要由CYP3A4在肝脏和肠壁代谢阿托伐他汀,少量由CYP2C9、CYP2C19、CYP3A5和UGT1A1代谢。阿托伐他汀酸由CYP3A代谢产生邻、对位羟基活性代谢产物,在体内它们与各自的非活性内酯形式处于平衡状态。ABCB1(编码p-gp)和ABCG2(编码BCRP)介导阿托伐他汀及其代谢物从肝脏排入胆汁后消除(图1)[1]。
Research progress of atorvastatin gene polymorphism
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摘要: 阿托伐他汀是临床上广泛使用的调血脂药物,长期使用能够预防并减少动脉粥样硬化性心血管疾病(ASCVD)的发生,但阿托伐他汀的疗效具有显著的个体间差异,有些个体不能达到预期调脂目标值或出现严重的不良反应。这与个体间的遗传多样性有关,遗传变异可导致药物体内处置不同,从而导致临床疗效和不良反应有差异。对影响阿托伐他汀药物反应的药物代谢酶、药物转运体、药物作用靶点及与脂质代谢相关基因多态性加以综述,并从基因水平上探讨不同个体使用阿托伐他汀的药动学、药效学及不良反应易感性差别的原因。Abstract: Atorvastatin is a blood lipid-lowering drug widely used clinically. Long-term use can prevent and reduce the occurrence of atherosclerotic cardiovascular disease (ASCVD). However, the efficacy of atorvastatin has significant inter-individual differences. Some individuals failed to achieve the expected lipid-lowering target value or had serious adverse reactions, which were related to the genetic diversity between individuals. Genetic variation can lead to differences in drug configuration, clinical efficacy and adverse reactions. The drug metabolism enzymes, drug transporters, drug targets and genetic polymorphisms related to lipid metabolism were reviewed in this paper that affect the drug response of atorvastatin, and from the gene level to explore the reasons for the differences in the pharmacokinetics, pharmacodynamics and susceptibility to adverse reactions of different individuals using atorvastatin.
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Key words:
- atorvastatin /
- blood lipids /
- drug metabolizing enzymes /
- drug transporters /
- gene polymorphisms
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