Irinotecan pathway

This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A1*28) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity. Source: [http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp PharmGkb]

本途径展示了化疗前药伊立替康的生物转化过程，形成活性代谢物SN-38，该代谢物为DNA拓扑异构酶I的抑制剂。SN-38主要通过UGT1A1（催化胆红素糖苷化）将活性代谢物SN-38糖苷化成无活性形式。伊立替康用于治疗转移性结直肠癌、小细胞肺癌以及其他多种实体瘤。患者对伊立替康的反应存在较大差异，以及严重的副作用，如腹泻和中性粒细胞减少，部分原因可能在于代谢酶和转运蛋白的遗传变异。影响该途径的已知变异包括UGT1A1启动子多态性重复序列（UGT1A1*28）以及ABCB1基因中的1236C>T多态性。虽然UGT1A1*28基因型与毒性相关，但需要进一步证据来描述ABCB1变异在毒性中的作用。来源：[http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp PharmGkb]