Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
J Clin Pharmacol. 2022 Sep;62(9):1160-1169. doi: 10.1002/jcph.2059. Epub 2022 May 6.
Irinotecan-induced hepatotoxicity can cause severe clinical complications in patients; however, the underlying mechanism and factors affecting hepatotoxicity have rarely been investigated. In this cross-sectional study, we screened all clinical, demographic, medication, and genetic variables among 126 patients receiving irinotecan and explored potential associations with the incidence and time to onset of irinotecan-induced hepatotoxicity. Approximately 38.9% of the patients suffered from hepatotoxicity after irinotecan administration. The presence of cardiovascular diseases increases the incidence of hepatotoxicity ≈2.9-fold and doubles the hazard of time to hepatotoxicity. Patients with liver metastasis had a >4-fold higher risk of hepatotoxicity and a 3.5-fold increased hazard of time to hepatotoxicity compared to those without liver metastasis. Patients who took cytochrome P450 (CYP) 3A inducers had a 4.4-fold increased incidence of hepatotoxicity, and furthermore, concomitant use of platinum-based antineoplastics revealed 4.2 times the hazard of time to hepatotoxicity compared to those receiving antimetabolites. The cumulative dose of irinotecan (5-9 cycles) increased hepatotoxicity by 8.5 times. However, the genotypes and phenotypes of UGT1A1*28/*6 failed to be predictive factors of hepatotoxicity. The findings of this study suggest that irinotecan-induced hepatotoxicity is not directly associated with genetic variables but is mostly related to concomitant use of CYP3A4 inducers and platinum, as well as the presence of liver metastasis and cardiovascular disease. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using CYP3A inducers and platinum antineoplastic drugs, which may be the best way to prevent hepatotoxicity.
伊立替康诱导的肝毒性可导致患者发生严重的临床并发症，但肝毒性的潜在机制和影响因素尚未得到充分研究。在这项横断面研究中，我们筛选了接受伊立替康治疗的 126 例患者的所有临床、人口统计学、药物和遗传变量，并探讨了与伊立替康诱导的肝毒性的发生率和发病时间相关的潜在因素。约 38.9%的患者在使用伊立替康后出现肝毒性。心血管疾病的存在使肝毒性的发生率增加约 2.9 倍，使肝毒性的发病时间风险增加 1 倍。与无肝转移的患者相比，有肝转移的患者发生肝毒性的风险增加了>4 倍，肝毒性的发病时间风险增加了 3.5 倍。细胞色素 P450（CYP）3A 诱导剂的使用者发生肝毒性的风险增加了 4.4 倍，此外，与使用抗代谢药物相比，同时使用铂类抗肿瘤药物使肝毒性的发病时间风险增加了 4.2 倍。伊立替康（5-9 个周期）的累积剂量增加了 8.5 倍肝毒性的风险。然而，UGT1A1*28/*6 的基因型和表型未能成为肝毒性的预测因素。本研究结果表明，伊立替康诱导的肝毒性与遗传变量无直接关系，主要与 CYP3A4 诱导剂和铂类药物的同时使用以及肝转移和心血管疾病的存在有关。因此，建议密切监测肝功能，特别是在肝功能受损或使用 CYP3A 诱导剂和铂类抗肿瘤药物的患者中，这可能是预防肝毒性的最佳方法。
