Pharmacotherapeutics Unit, Department of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
Pharmacogenomics. 2012 Dec;13(16):1979-88. doi: 10.2217/pgs.12.165.
Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.
药物反应的个体间差异和不良反应的出现是癌症治疗中治疗失败的主要原因。功能性膜药物转运体在改变药代动力学特征、治疗耐药性、毒性和患者生存方面发挥着重要作用。这些转运体的遗传药理学研究有望为优化治疗提供新方法。紫杉烷类药物被批准用于治疗各种癌症。循环中的紫杉烷类药物被 SLCO1B3 摄取到肝细胞中。CYP450 酶 CYP3A4、CYP3A5 和 CYP2C8 负责将紫杉烷类药物转化为其代谢物。最终，ABCB1 和 ABCC2 将代谢物排入胆小管。编码参与紫杉烷类药物转运和清除的蛋白的基因的多态性会减少药物的排泄，导致患者出现毒性。这篇综述讨论了影响紫杉烷类药物药代动力学和毒性的转运体的遗传变异，为个体化医学的未来方向提供了见解。
