Pharmacokinetics of Gefitinib: Roles of Drug Metabolizing Enzymes and Transporters.
Pharmacokinetics of Gefitinib: Roles of Drug Metabolizing Enzymes and Transporters.
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DOI：
10.2174/1567201813666160709021605
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发表时间：
2016-07
影响因子：
2.4
通讯作者：
Can Zhao;Shu-yan Han;Ping-ping Li
中科院分区：
文献类型：
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作者：
Can Zhao;Shu-yan Han;Ping-ping Li
吉非替尼（Iressa, AstraZeneca）已被广泛用于局部晚期或转移性非小细胞肺癌的治疗。关于其药代动力学，特别是代谢方面的研究已有大量报道。本文综述了吉非替尼的药代动力学特征：吸收、分布、代谢和排泄（ADME）。总体而言，吉非替尼达到最高血浆水平相对较快且分布广泛。它经过广泛的生物转化，主要以粪便排出，尿液中不到7%。CYP450酶在吉非替尼代谢过程中起关键作用。参与代谢的主要酶是CYP3A4，其他CYP450酶起次要作用。吉非替尼的高清除率可能通过降低药物浓度导致耐药。转运体外排增强和摄取减少是重要的耐药机制。参与吉非替尼药代动力学的转运体包括atp结合盒和溶质转运体超家族。了解吉非替尼的药代动力学特性可以为处理耐药和针对其个体间变异性进行个性化治疗提供有价值的新信息。
Gefitinib (Iressa, AstraZeneca) has been widely used for the treatment of locally advanced or metastatic non-small cell lung cancer. A number of studies have been reported on its pharmacokinetics profiles, especially on the metabolism. In this review, we have comprehensively summarized the pharmacokinetic characteristics of gefitinib: absorption, distribution, metabolism and excretion (ADME). Overall, gefitinib reached the maximum plasma level relatively fast and distributed extensively. It underwent extensive biotransformation and predominantly excreted in feces, with less than 7% in the urine. CYP450 enzymes played critical roles in the process of gefitinib metabolism. The major enzyme involved in the metabolism was CYP3A4, with other CYP450 enzymes playing a secondary role. A high clearance of gefitinib might result in drug resistance by lowering drug concentration. The enhanced efflux and decreased uptake by transporters were important resistance mechanisms. The transporters involved in pharmacokinetics of gefitinib consist of the ATP-binding cassette and the solute carrier superfamily. Understanding the pharmacokinetics property of gefitinib may provide valuable and new information for dealing with drug resistance and making personalized therapy regarding their interindividual variability.