Pharmacokinetic Interaction Between Imatinib and Metformin in Rats.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Naling Fan, Liying Du, Teng Guo, Mingfeng Liu, Xinran Chen
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引用次数: 0

Abstract

Background and objective: Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats.

Methods: Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software.

Results: After single-dose co-administration of imatinib and metformin on day 1, the AUC0-24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0-24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05).

Conclusion: With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.

大鼠体内伊马替尼与二甲双胍的药代动力学相互作用
背景和目的:伊马替尼主要通过有机阳离子转运体 1(OCT1)、有机阴离子转运多肽 1B3(OATP1B3)和新型有机阳离子转运体 2(OCTN2)转运到肝脏,这是伊马替尼代谢和消除的第一步。服用伊马替尼的患者可同时服用二甲双胍(OCT1的底物)。伊马替尼和二甲双胍之间可能会发生药物相互作用(DDI),从而影响伊马替尼的临床疗效。本实验旨在研究二甲双胍对大鼠体内伊马替尼及其活性代谢产物N-去甲基伊马替尼的药代动力学影响:选取 20 只健康 Sprague-Dawley 大鼠,随机分为对照组和实验组(每组 10 只)。对照组口服伊马替尼(30 毫克/千克)14 天,实验组口服伊马替尼(30 毫克/千克)和二甲双胍(200 毫克/千克)14 天。大鼠血浆中伊马替尼和N-去甲基伊马替尼的浓度采用超高效液相色谱-质谱法测定。药代动力学参数由 DAS2.0 软件计算:实验组大鼠在第1天单次服用伊马替尼和二甲双胍后,伊马替尼的AUC0-24(血浆浓度-时间曲线下面积)和Cmax(最大浓度)以及N-去甲基伊马替尼的MRT(平均停留时间)和Cmax与对照组相比均显著下降(P<0.05)。多剂量联合服用伊马替尼和二甲双胍14天后,实验组伊马替尼和N-去甲基伊马替尼的AUC0-24和Cmax均明显下降(P<0.05):结论:无论是单次给药还是多次给药,二甲双胍都会显著改变伊马替尼和N-去甲基伊马替尼的药代动力学参数。结果表明,二甲双胍和伊马替尼联合用药时应谨慎。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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