Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Eur J Drug Metab Pharmacokinet. 2024 Sep;49(5):631-644. doi: 10.1007/s13318-024-00909-0. Epub 2024 Aug 6.
Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement.
The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg).
Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 μM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) C and area under the plasma concentration-time curve (AUC), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC.
The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.
由于质子泵抑制剂的联合应用，许多临床医生对乳腺癌患者使用细胞周期蛋白依赖性激酶 4/6 抑制剂后潜在的药物作用恶化表示担忧。因此，本研究评估了质子泵抑制剂对帕博西尼和瑞博西尼的药代动力学的影响，特别是细胞色素 P450（CYP）3A4 和 P-糖蛋白参与的情况。
采用分子对接、大鼠肝微粒体代谢稳定性试验、人重组 CYP3A4（rCYP3A4）酶和 Caco-2 细胞单层，以及奥美拉唑和雷贝拉唑（分别为 5 和 10 mg/kg）预处理 30 分钟和 7 天后，口服给予帕博西尼和瑞博西尼（10 mg/kg），研究奥美拉唑和雷贝拉唑对这些药物的药物代谢和外排作用。
奥美拉唑和雷贝拉唑在 30 μM 时抑制 rCYP3A4 衣壳酶的活性，抑制率为 50-60%。此外，奥美拉唑和雷贝拉唑（10 μM）均显著降低了帕博西尼和瑞博西尼的 P-糖蛋白介导的药物外排。奥美拉唑以 10 mg/kg 的剂量预处理 7 天，可使帕博西尼的平均最大血浆浓度（Cmax）分别降低 24%和 26%，AUC 分别降低 24%和 26%。雷贝拉唑预处理对帕博西尼的药代动力学没有显著影响；然而，瑞博西尼的药代动力学显示 AUC 增加了 83.94%。
研究结果表明，长期使用治疗剂量的奥美拉唑和雷贝拉唑均可改变帕博西尼和瑞博西尼的药代动力学。雷贝拉唑的联合应用可能通过 CYP 酶和 P-糖蛋白抑制改变帕博西尼和瑞博西尼的药代动力学。
