Pharmacogenetics of irinotecan metabolism and transport: An update

被引:149
作者
Smith, NF
Figg, WD
Sparreboom, A
机构
[1] NCI, Clin Pharmacol Res Core, Med Oncol Branch, Bethesda, MD 20892 USA
[2] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD USA
关键词
CPT-11; SN-38; CYP3A; CES; UGT1A; ABCB1; ABCC1; ABCC2; ABCG2;
D O I
10.1016/j.tiv.2005.06.045
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
The anticancer agent irinotecan (CPT- 11) is converted to SN-38, which is approximately 100 to 1000-fold more cytotoxic than the parent drug. The pharmacokinetics of irinotecan are extremely complex and have been the subject of intensive investigation in recent years. Irinotecan is subject to extensive metabolism by various polymorphic enzymes, including CES2 to form SN-38, members of the UGT1A subfamily, and CYP3A4 and CYP3A5, which form several pharmacologically inactive oxidation products. Elimination of irinotecan is also dependent on drug-tran sporting proteins, notably ABCB1 (P-glycoprotein), ABCC2 (cMOAT) and ABCG2 (BCRP), present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. This report provides an update on current strategies to individualize irinotecan chemotherapy based on each patient's genetic constitution, which may ultimately lead to more selective use of this agent. Published by Elsevier Ltd.
引用
收藏
页码:163 / 175
页数:13
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