Pharmaceutical excipients (PEs) are substances included in drug formulations. Recent studies have revealed that some PEs can affect the activity of metabolic enzymes and drug transporters; however, the effects of PEs on CYP2C8 and its interaction potential with drugs remain unclear. In this study, we evaluated the effects of Tween 80 and EL−35 on CYP2C8 in vitro and further investigated their impacts on the PK of paclitaxel (PTX) in rats after single or multiple doses. The in vitro study indicated that Tween 80 and EL−35 inhibited CYP2C8 activity in human and rat liver microsomes. EL−35 also decreased the expression of CYP2C8 in HepG2 cells. In the in vivo study, Tween 80 did not alter the PK of PTX after single or multiple doses, whereas EL−35 administered for 14 days significantly increased the AUC and MRT of PTX. Further analysis indicated that multiple-dose EL−35 reduced the expression of Cyp2c22 and production of 6-OH-PTX in the rat liver. Our study suggested that short-term exposure to both PEs did not affect the PK of PTX in rats, but multiple doses of EL−35 increased the AUC and MRT of PTX by downregulating the hepatic expression of Cyp2c22. Such effects should be taken into consideration during drug formulation and administration.

中文翻译：

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评估 CYP2C8 介导的药物赋形剂-药物相互作用潜力：吐温 80 和 Cremophor EL-35 的案例研究

药用辅料 (PE) 是包含在药物制剂中的物质。最近的研究表明，一些PEs可以影响代谢酶和药物转运蛋白的活性；然而，PEs 对 CYP2C8 的影响及其与药物的相互作用潜力仍不清楚。在本研究中，我们在体外评估了吐温 80 和 EL-35 对 CYP2C8 的影响，并进一步研究了它们对大鼠单次或多次给药后紫杉醇 (PTX) PK 的影响。体外研究表明，吐温 80 和 EL-35 抑制人和大鼠肝微粒体中的 CYP2C8 活性。EL-35 还降低了 HepG2 细胞中 CYP2C8 的表达。在体内研究中，吐温 80 在单次或多次给药后没有改变 PTX 的 PK，而 EL-35 给药 14 天显着增加了 PTX 的 AUC 和 MRT。进一步分析表明，多剂量 EL-35 降低了大鼠肝脏中 Cyp2c22 的表达和 6-OH-PTX 的产生。我们的研究表明，短期暴露于两种 PE 不影响大鼠 PTX 的 PK，但多剂量 EL-35 通过下调 Cyp2c22 的肝脏表达增加 PTX 的 AUC 和 MRT。在药物配制和给药过程中应考虑到这些影响。