来氟米特药物代谢酶和转运体的基因组学研究进展

来氟米特是一种用于治疗免疫系统疾病的免疫调节剂，但由于存在药物不良反应，超过50%的患者在用药1年后停用该药。目前，药物遗传学研究表明单核苷酸多态性（SNPs）对来氟米特血药浓度有一定的影响，与类风湿性关节炎（RA）患者的有效性和耐受性存在潜在相关。体外研究表明，细胞色素P450酶CYP1A2、CYP2C19和CYP3A4参与来氟米特在机体内的代谢，CYP1A2*1F等位基因可能与RA患者的来氟米特不良反应相关。此外，二氢乳清酸脱氢酶（DHODH）基因rs3213422（19C>A）的C等位基因和雌激素受体（ESR1/2）的基因多态性可能与来氟米特的不良反应和治疗效果相关。本文总结了参与来氟米特体内过程相关代谢酶及转运体的基因多态性与来氟米特及其活性代谢物特立氟胺血药浓度、临床疗效以及药物不良反应的相关性，为深入研究来氟米特临床合理用药提供参考信息。

Advances in the research of pharmacogenomics on the drug metabolic enzymes and transporters of leflunomide

Leflunomide is an immunomodulator used to treat diseases of the immune system. More than 50% of patients discontinued leflunomide within one year due to adverse drug reaction. Currently, pharmacogenetic studies have shown that single nucleotide polymorphisms (SNPs) have an impact on leflunomide plasma concentrations, and could be associated with efficacy and tolerability in patients with rheumatoid arthritis (RA). In vitro studies have demonstrated that cytochromes P450(CYPs), mainly CYP1A2, CYP2C19 and CYP3A4, are involved in leflunomide metabolism. It was shown that CYP1A2*1F allele may be associated with leflunomide adverse drug reactions (ADR) in patients with RA. In addition, the C allele of dihydroorotate dehydrogenase (DHODH) gene SNP rs3213422(19C>A) and oestrogen receptor (ESR1/2) polymorphism may be associated with leflunomide ADR and therapeutic effect. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of leflunomide with the active metabolite teriflunomide concentration, clinical efficacy and adverse drug reaction, which provides reference for in-depth pharmacogenomic study and clinical use of leflunomide.