Kim Tae Won, Innocenti Federico
Section of Oncology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea.
Ther Drug Monit. 2007 Jun;29(3):265-70. doi: 10.1097/FTD.0b013e318068623b.
Irinotecan is widely used in the treatment of metastatic colorectal cancer and extensive small-cell lung cancer. Its use is limited by severe toxicities such as neutropenia and delayed-type diarrhea. Irinotecan is converted to its active metabolite SN-38. SN-38 is further metabolized to SN-38G by various hepatic and extrahepatic UGT1A isozymes, mainly UGT1A1. Impaired glucuronidation activity of the UGT1A1 enzyme has been linked with elevated levels of SN-38, leading to toxicities. UGT1A128 involves an extra TA repeat in the UGT1A1 promoter region and is the variant most frequently contributing to interpatient variability in irinotecan pharmacokinetics and toxicities. This information led to the revision of the irinotecan label by the US Food and Drug Administration. Recently, UGT1A16 seems to contribute to the risk of toxicity of irinotecan in Asian patients. The pharmacogenetics of irinotecan (irinogenetics) is one of few promising examples of the application of pharmacogenetics to individualized drug therapy. This review summarizes ongoing studies and unanswered questions on irinogenetics.
伊立替康广泛用于治疗转移性结直肠癌和广泛期小细胞肺癌。其应用受到严重毒性的限制，如中性粒细胞减少和迟发型腹泻。伊立替康转化为其活性代谢产物SN - 38。SN - 38通过各种肝内和肝外UGT1A同工酶进一步代谢为SN - 38G，主要是UGT1A1。UGT1A1酶的葡萄糖醛酸化活性受损与SN - 38水平升高有关，从而导致毒性。UGT1A128在UGT1A1启动子区域涉及一个额外的TA重复序列，是导致伊立替康药代动力学和毒性个体间差异最常见的变异体。这一信息导致美国食品药品监督管理局对伊立替康的标签进行了修订。最近，UGT1A16似乎与亚洲患者中伊立替康的毒性风险有关。伊立替康的药物遗传学（伊立替康遗传学）是药物遗传学应用于个体化药物治疗的少数有前景的例子之一。本综述总结了关于伊立替康遗传学的正在进行的研究和未解决的问题。
