Abstract Context: Hydroxycamptothecin (HCPT) has antitumor activity in various cancers, but its poor bioavailability and efflux limit its clinical application. Verapamil has been demonstrated to improve the bioavailability of many drugs. However, the effect of verapamil on the pharmacokinetics of HCPT was not clear. Objective: The effect of verapamil on the pharmacokinetics of HCPT was investigated to clarify the drug–drug interaction between HCPT and verapamil. Materials and methods: The pharmacokinetic profiles of oral administration of HCPT (50 mg/kg) in two group of Sprague–Dawley rats (six rats each), with pre-treatment of verapamil (10 mg/kg/day) for 7 days were investigated, with the group without verapamil pre-treatment as control. Additionally, the metabolic stability and transport of HCPT in the presence or absence of verapamil were also investigated with the employment of the rat liver microsomes and Caco-2 cell transwell model. Results: Verapamil significantly increased the peak plasma concentration (from 91.97 ± 11.30 to 125.30 ± 13.50 ng/mL), and decrease the oral clearance (from 63.85 ± 10.79 to 32.95 ± 6.17 L/h/kg). The intrinsic clearance rate was also significantly decreased (from 39.49 ± 0.42 to 28.64 ± 0.30 μL/min/mg protein) by the preincubation of verapamil. The results of Caco-2 cell transwell experiments showed the efflux of HCPT was inhibited by verapamil, as the efflux ratio decreased from 1.82 to 1.21. Discussion and conclusions: The system exposure of HCPT was increased by verapamil. Verapamil may exert this effect through inhibiting the activity of CYP3A4 or P-gp, which are related to the metabolism and transport of HCPT.

中文翻译：

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维拉帕米对羟基喜树碱药代动力学的影响及其潜在机制

摘要 背景：羟基喜树碱（HCPT）在多种癌症中具有抗肿瘤活性，但其生物利用度和外排性较差，限制了其临床应用。维拉帕米已被证明可以提高许多药物的生物利用度。然而，维拉帕米对 HCPT 药代动力学的影响尚不清楚。目的：研究维拉帕米对 HCPT 药代动力学的影响，以阐明 HCPT 与维拉帕米之间的药物相互作用。材料和方法：两组 Sprague-Dawley 大鼠（每组 6 只）口服 HCPT（50 毫克/千克），维拉帕米（10 毫克/千克/天）预处理 7 天的药代动力学特征是以未经维拉帕米预处理的组为对照。此外，还使用大鼠肝微粒体和 Caco-2 细胞 transwell 模型研究了存在或不存在维拉帕米时 HCPT 的代谢稳定性和转运。结果：维拉帕米显着增加血浆峰值浓度（从 91.97 ± 11.30 到 125.30 ± 13.50 ng/mL），并降低口服清除率（从 63.85 ± 10.79 到 32.95 ± 6.17 L/h/kg）。维拉帕米的预孵育也显着降低了内在清除率（从 39.49 ± 0.42 到 28.64 ± 0.30 μL/min/mg 蛋白质）。Caco-2细胞transwell实验结果表明，维拉帕米抑制了HCPT的外排，外排比从1.82降至1.21。讨论和结论：维拉帕米增加了HCPT的系统暴露。维拉帕米可能通过抑制 CYP3A4 或 P-gp 的活性发挥这种作用，