维拉帕米,一种P-糖蛋白-1和细胞色素P4503A4抑制剂,对瑞普替尼药代动力学和代谢稳定性的影响:一项大鼠药物相互作用研究。

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Shyamala Mudavath, Dongamanti Ashok
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引用次数: 0

摘要

背景和目的:瑞普替尼被开发用于靶向在某些癌症和骨髓增生性肿瘤,特别是胃肠道间质瘤(GIST)中发现的一系列KIT原癌基因突变和血小板衍生生长因子受体a(PDGFR-a)激酶。本研究研究了维拉帕米(一种潜在的P-糖蛋白-1(P-gp1)和细胞色素P4503A4(CYP3A4)抑制剂)对瑞普替尼在大鼠体内的药代动力学的影响。本研究还评估了在维拉帕米存在下瑞普替尼的代谢稳定性和体外细胞吸收。方法:建立并验证了一种新的灵敏、省时的液相色谱-串联质谱法(LC-MS/MS)测定大鼠血浆中瑞普替尼的方法。Zorbax SB C18柱用于分离和分析瑞普替尼,流动相由50:50(%v/v)乙腈和10mM甲酸铵缓冲液组成,流速为0.4mL/min。在该方法中,伊马替尼被用作内标(IS)。通过在维拉帕米(10mg/kg体重)存在下成功地口服剂量为5mg/kg体重的瑞普替尼,在Wistar大鼠中评估了瑞普替尼药代动力学特征。随后,使用大鼠肝微粒体来评估维拉帕米对瑞普替尼代谢稳定性的影响,并使用Caco-2细胞transwell模型测试吸收。结果:瑞普替尼和IS通过质谱多重反应监测(MRM)模式进行鉴定,显示离子跃迁为510.09→94.06 m/z和494.26→ 分别为394.16m/z。高效液相色谱法分别在0.91和0.68分钟的保留时间成功洗脱了瑞普替尼和IS,该方法对所有参数进行了验证,并符合验收标准。维拉帕米联合给药使瑞普替尼的最大浓度(Cmax)从437±84 ng/mL增加到492±50 ng/mL(12%),从0到最后一次采样时间t的浓度-时间曲线下面积(AUC0-t)增加了约40.6%。研究结果还表明维拉帕米增加了瑞普替尼的代谢稳定性。结论:研究结果表明,瑞普替尼与CYP3A4和/或P-gp1抑制剂联合给药与影响瑞普替尼药代动力学的显著药物相互作用有关。建议对人类受试者进行进一步研究,以确认当与P-gp1/CYP3A4抑制剂一起给药时,瑞普替尼的剂量调整和治疗药物监测,确保患者安全并优化瑞普替尼的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Effect of Verapamil, a P-glycoprotein-1 and Cytochrome P450 3A4 Inhibitor, on Pharmacokinetics and Metabolic Stability of Ripretinib: A Drug-Drug Interaction Study in Rats.

Effect of Verapamil, a P-glycoprotein-1 and Cytochrome P450 3A4 Inhibitor, on Pharmacokinetics and Metabolic Stability of Ripretinib: A Drug-Drug Interaction Study in Rats.

Background and objectives: Ripretinib was developed to target a whole range of KIT proto-oncogene mutations and platelet-derived growth factor receptor A (PDGFR-A) kinases found in certain cancers and myeloproliferative neoplasms, particularly gastrointestinal stromal tumours (GISTs). This study investigated the effect of verapamil, a potential inhibitor of P-glycoprotein-1 (P-gp1) and cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics of ripretinib in rats when administered orally together. This study also assessed the metabolic stability and in vitro cellular absorption of ripretinib in the presence of verapamil.

Methods: A novel sensitive time-saving liquid chromatography tandem mass spectometry (LC-MS/MS) technique for determining ripretinib in rat plasma was developed and validated. A Zorbax SB C18 column was used for the separation and analysis of ripretinib with a mobile phase consisting of 50:50 (%v/v) acetonitrile and 10 mM ammonium formate buffer at a flow rate of 0.4 mL/min. Imatinib was used as an internal standard (IS) in the method. The pharmacokinetic characteristics of ripretinib were evaluated in Wistar rats by successfully administering an oral dosage of 5 mg/kg body weight of ripretinib in the presence of verapamil (10 mg/kg body weight). Subsequently, rat liver microsomes were used to assess the effect of verapamil on ripretinib metabolic stability, and absorption was tested using a Caco-2 cell transwell model.

Results: Ripretinib and IS were identified using multiple reaction monitoring (MRM) modes by mass spectrometry and showed ion transitions of 510.09→94.06 m/z and 494.26→ 394.16 m/z, respectively. The high-performance liquid chromatography (HPLC) method successfully eluted ripretinib and IS at retention times of 0.91 and 0.68 min, respectively, and the method was validated for all parameters and met the criteria for acceptance. Co-administration of verapamil increased the maximum concentration (Cmax) of ripretinib from 437 ± 84 ng/mL to 492 ± 50 ng/mL (12%), and the area under the concentration-time curve from 0 to the last sampling time t (AUC0-t) increased by approximately 40.6%. Verapamil significantly reduced the basolateral-to-apical transfer of ripretinib through Caco-2 cells. Findings also showed that verapamil increased the metabolic stability of ripretinib.

Conclusion: The study results indicate that the co-administration of ripretinib with CYP3A4 and/or P-gp1 inhibitors is associated with significant drug-drug interactions that affect the pharmacokinetics of ripretinib. Further research in human subjects is suggested to confirm dosage adjustment and therapeutic drug monitoring of ripretinib when administered along with P-gp1/CYP3A4 inhibitors ensuring patient safety and optimizing the therapeutic benefits of ripretinib.

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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.
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