Elewa Hazem, Wilby Kyle John
College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar.
Eur J Drug Metab Pharmacokinet. 2017 Oct;42(5):745-756. doi: 10.1007/s13318-016-0399-1.
Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.
已知药物代谢酶和药物转运体的基因变异性会影响许多药物的药代动力学。抗疟药物是一类已知利用易发生基因变异的代谢和消除途径的药物。本文旨在综述影响抗疟药物的基因变异，并讨论其临床意义。已确定了编码细胞色素P450（CYP）酶的基因数据：CYP2C8、CYP2C19、CYP2A6、CYP2D6、CYP2B6以及P-糖蛋白药物转运体。在CYP2C8代谢降低的患者中，阿莫地喹的不良反应更为常见。CYP2C19变异影响了氯胍的代谢，但未观察到疗效结果的差异。CYP2A6的超快代谢者青蒿琥酯（活性代谢物双氢青蒿素的前体药物）不良反应的发生率增加。在依法韦仑存在的情况下，CYP2B6的突变影响了达到第7天卤泛群浓度高于公认治疗临界值的患者数量。在奈韦拉平存在的情况下，卤泛群浓度也受ABCB1变异的影响。确定的最关键的药物遗传学考虑因素是葡萄糖-6-磷酸脱氢酶缺乏与在用伯氨喹或氯胍-氨苯砜-青蒿琥酯联合治疗的患者中发生溶血性贫血和血红蛋白水平降低之间的关联。这些发现表明，需要密切监测来自代谢酶基因变异普遍存在人群的患者，以确保获得最佳临床结果。未来的研究应确定哪些人群发生潜在治疗失败和/或不良反应的风险最大，哪些药物最易受代谢酶基因变异的影响，以及基因影响对一线治疗方案疗效和安全性的影响。
