伊曲康唑对舒尼替尼药代动力学的影响及其机制。
Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.
机构信息
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
出版信息
BMC Cancer. 2024 Sep 11;24(1):1131. doi: 10.1186/s12885-024-12904-4.
BACKGROUND
Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort.
METHODS
The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro.
RESULTS
Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC, AUC, and T rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib.
CONCLUSIONS
Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.
背景
舒尼替尼是一种新开发的多靶点酪氨酸激酶抑制剂（TKI），已成为治疗晚期肾细胞癌（RCC）的常用治疗选择。本研究旨在探讨舒尼替尼与伊曲康唑相互作用的机制。
方法
采用超高效液相色谱串联质谱法（UPLC-MS/MS）分析和定量检测舒尼替尼及其主要代谢物 N-去乙基舒尼替尼的浓度。我们使用大鼠肝微粒体（RLM）、人肝微粒体（HLM）和体内大鼠模型评估伊曲康唑与舒尼替尼之间的潜在相互作用。在体内研究中，将两组（n=5）SD 大鼠随机分为舒尼替尼组和舒尼替尼联合伊曲康唑组。此外，还在体外 RLM 中研究了伊曲康唑对舒尼替尼和 N-去乙基舒尼替尼代谢稳定性的影响。
结果
研究结果表明，在 RLM 中，伊曲康唑表现出混合性非竞争性和竞争性抑制机制，IC（半最大抑制浓度）值为 1.33 μM。而在 HLM 中，伊曲康唑表现出竞争性抑制机制，IC 值为 5.30 μM。体内研究表明，伊曲康唑的存在显著增加了舒尼替尼的药代动力学特征，与对照组（单独给予 5mg/kg 舒尼替尼）相比，AUC、C 和 T 分别升高约 211.38%、203.92%和 288.89%。在伊曲康唑存在的情况下，代谢物 N-去乙基舒尼替尼的药代动力学特征与对照组相比基本保持不变。此外，体外代谢稳定性实验表明，伊曲康唑抑制了舒尼替尼和 N-去乙基舒尼替尼的代谢处理。
结论
伊曲康唑对舒尼替尼的代谢有重要影响，为舒尼替尼的精确治疗给药提供了基础信息。
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