Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;, Email:
Pharmazie. 2020 May 1;75(5):186-190. doi: 10.1691/ph.2020.0316.
Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and MDR1 and its effect the irinotecan treatment . However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions and . After treatment with 10 mg·kg CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC increased significantly. The AUC (SN-38G)/AUC (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC of CsA for UGT1A1 enzyme was 9.4 μM. Furthermore, the UGT1A1 mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving irinotecan's treatment index.
伊立替康（CPT-11）是一种广谱药物，可用于治疗实体瘤恶性肿瘤，但严重的腹泻限制了其广泛应用。SN-38 在小肠中的局部作用被认为是导致伊立替康引起的迟发性腹泻的原因。有人提出环孢素 A（CsA）抑制胆汁排泄可以减轻这种副作用，但实际上并不能提高伊立替康的治疗指数。目前，大多数研究都集中在 CsA 通过转运蛋白 MRP2 和 MDR1 抑制胆汁排泄及其对伊立替康治疗的影响。然而，尿苷二磷酸葡萄糖醛酸转移酶 1 多肽 A1（UGT1A1）与伊立替康及其代谢物的显著改变处置有关，因此与伊立替康诱导的毒性有关。本研究集中于 UGT1A1 介导的 SN-38 向 SN-38G 的转化，并系统研究了 CsA-伊立替康的相互作用。用 10mg·kg CsA 治疗 7 天后，伊立替康及其代谢物的胆汁排泄减少，AUC 显著增加。与 vehicle 处理的大鼠相比，AUC（SN-38G）/AUC（SN-38）显著降低。在肝微粒体孵育系统中，CsA 对 UGT1A1 酶的 IC 为 9.4μM。此外，UGT1A1mRNA 和蛋白表达水平显著降低。本研究表明，CsA 治疗可通过抑制 UGT1A1 酶增加 SN-38 的全身暴露和毒性。UGT1A1 酶的抑制可能是 CsA 改善伊立替康治疗指数失败的关键因素。
