The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY European Journal of Drug Metabolism and Pharmacokinetics Pub Date : 2024-09-01 Epub Date: 2024-08-06 DOI:10.1007/s13318-024-00909-0
Prajakta Harish Patil, Mrunal Desai, Sumit Birangal, Gautham Shenoy Gurupur, Mahadev Rao, Anandkumar Yadav, Vishwanath Kurawattimath, Avinash Chaudhari, Tarun Sharma, Jakir Pinjari, Jagadish Puralae Channabasavaiah
{"title":"The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.","authors":"Prajakta Harish Patil, Mrunal Desai, Sumit Birangal, Gautham Shenoy Gurupur, Mahadev Rao, Anandkumar Yadav, Vishwanath Kurawattimath, Avinash Chaudhari, Tarun Sharma, Jakir Pinjari, Jagadish Puralae Channabasavaiah","doi":"10.1007/s13318-024-00909-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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<sub>max</sub> and area under the plasma concentration-time curve (AUC<sub>0-24 h</sub>), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC<sub>0-24 h</sub>.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"631-644"},"PeriodicalIF":1.9000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365823/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-024-00909-0","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/6 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Background and objectives: 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.

Methods: 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).

Results: 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) Cmax and area under the plasma concentration-time curve (AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h.

Conclusion: 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.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
同时服用质子泵抑制剂对大鼠 CDK4/6 抑制剂药代动力学的影响:对评估肝脏和转运体介导的药物间相互作用的启示
背景和目的:临床上对乳腺癌患者合用质子泵抑制剂可能导致细胞周期蛋白依赖性激酶4/6抑制剂效果恶化表示了许多担忧。因此,本研究从细胞色素P450(CYP)3A4和P-糖蛋白参与的角度评估了质子泵抑制剂对帕博昔利(palbociclib)和瑞博昔利(ribociclib)药代动力学的影响:方法:采用分子对接、大鼠肝脏微粒体代谢稳定性试验、人重组 CYP3A4(rCYP3A4)酶和 Caco-2 细胞单层膜,研究了奥美拉唑和雷贝拉唑对这些药物代谢和外流的影响、和 Caco-2 细胞单层中的代谢稳定性检测,以及在口服帕博昔利(palbociclib)和瑞博昔利(ribociclib)(10 毫克/千克)前 30 分钟和 7 天使用奥美拉唑和雷贝拉唑(5 毫克/千克和 10 毫克/千克)的体内药代动力学。结果奥美拉唑和雷贝拉唑可抑制rCYP3A4 baculosomes中CYP3A4酶的活性,30 μM时抑制率为50-60%。此外,奥美拉唑和雷贝拉唑(10 μm)都能显著减少P-糖蛋白介导的帕博西尼和利博西尼的药物外流。奥美拉唑剂量为10毫克/千克,预处理7天后,帕博昔利的平均最大血浆浓度(Cmax)和血浆浓度-时间曲线下面积(AUC0-24小时)分别降低了24%和26%。帕博昔利的药代动力学没有因雷贝拉唑的预处理而发生明显改变;但瑞博昔利的药代动力学显示AUC0-24 h增加了83.94%:研究结果表明,长期服用治疗剂量的奥美拉唑和雷贝拉唑可改变帕博昔单抗和瑞博昔单抗的药代动力学。同时服用雷贝拉唑可能会通过CYP酶和P-糖蛋白抑制作用改变帕博昔利和瑞博昔利的药代动力学。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
期刊最新文献
Assessment of Piperacillin-Tazobactam Population Pharmacokinetic Models in Neonates: An External Validation. Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults. Evaluation of the Clinical Outcomes of Cyclosporine Short Infusion Versus Continuous Infusion Postallogenic Stem Cell Transplantation. Hypertensive Nephropathy Changes the Expression of Drug-Metabolizing Enzymes and Transporters in Spontaneously Hypertensive Rat Liver and Kidney. Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1