硫嘌呤类药物的遗传药理学研究及其在儿科相关疾病中的正确应用

Genetic pharmacology and optimized application of thiopurines in pediatric patients

硫嘌呤类药物是常用的免疫抑制剂,广泛应用于儿童急性淋巴细胞白血病、炎症性肠病的治疗,但以骨髓抑制、肝毒性为主的不良反应限制了临床应用。巯嘌呤的体内代谢转化和处置过程由包括巯嘌呤-S-甲基转移酶(thiopurine methyltransferase,TPMT)、裸子水解酶(nudix hydrolase 15,NUDT15)、三磷酸肌苷焦磷酸酶(inosine triphosphate pyrophosphohydrolase,ITPA)和多药耐药相关蛋白(multidrug resistance-associated protein,MRP4)的精确调控。上述药物代谢酶和转运体的遗传药理学研究结果连同对活性药物的浓度监测的研究,可以解释部分个体之间的治疗作用或不良反应的差异。文章对硫嘌呤类药物相关遗传药理学和活性代谢物的治疗药物监测研究进行全面地分析、归纳和总结,为优化巯嘌呤类药物的治疗方案、推动个体化精准用药提供新的思路。

Thiopurine drugs 6-mercaptopurine(6-MP),thioguanine(TG)and azathioprine(AZA)are widely used immunosuppressive treatment in pediatric patients with inflammatory bowel disease(IBD)and acute lymphoblastic leukemia(ALL).However,the incidence of adverse reactions especially myelosuppression and hepatotoxicity is high. The metabolism and transformation of thiopurine drugs are mediated by thiopurine S-methyltransferase(TPMT),nudix hydrolase 15(NUDT15),inosine triphosphate pyrophosphohydrolase(ITPA)and multidrug resistance-associated protein(MRP4). Genetic polymorphisms in genes encoding above-mentioned drug-metabolizing enzymes and transporter proteins can significantly influence the pharmacokinetics and pharmacological effects of thiopurines and can be significant determinants of the efficacy and toxicity of therapy. There is still a gap between the current drug treatment strategy and precise clinical application of thiopurines. In this article,we review the studies of pharmacogenetics of thiopurines and therapeutic drug monitoring of active metabolites to provide a new insight into the precise clinical application to thiopurines.