Pharmacokinetics of Trelagliptin in Rats after Exposure to Acute and Chronic High Altitude Hypoxia.

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current drug metabolism Pub Date : 2025-01-01 DOI:10.2174/0113892002408318251002114813

Zhilan Huan, Delong Duo, Ni Zhao, Ye Chang, Guiqin Xu, Xue Wu, Yafeng Wang

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引用次数: 0

Abstract

Background: As a long-acting DPP-4 inhibitor administered orally once a week, trelagliptin can address the issues of frequent medication and poor compliance associated with traditional hypoglycemic drugs.

Methods: The Hypoxia model in rats was constructed at an altitude of approximately 4300 meters. The plasma concentration of trelagliptin was determined by LC-MS/MS. The biochemical indices and the protein expression levels of P-gp and OCT2 in the kidneys of rats were determined to explain the possible reasons for the pharmacokinetic changes of trelagliptin.

Results: This study demonstrated that the pharmacokinetic parameters of trelagliptin were significantly changed in high-altitude hypoxic environments. Compared with the control group, the AUC, MRT, t1/2, and Vd were remarkably increased during acute and chronic hypoxia, while the CL and Ke were decreased. Additionally, the biochemical indexes and protein expression of P-gp and OCT2 were significantly altered.

Conclusion: The study demonstrated that high-altitude hypoxia significantly altered trelagliptin's pharmacokinetics, slowing clearance, prolonging elimination half-life and residence time, and increasing bioavailability. These changes suggested that the optimal therapeutic dosage of trelagliptin should be reassessed under hypoxic exposure.

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Trelagliptin在急性和慢性高原缺氧大鼠体内的药代动力学。

目的：trelagliptin是一种长效DPP-4抑制剂，每周口服1次，可以解决传统降糖药频繁用药和依从性差的问题。揭示trelagliptin的药代动力学变化对高海拔低氧环境人群尤为重要。方法：在海拔约4300米处建立大鼠缺氧模型。采用LC-MS/MS法测定特列列汀血药浓度。测定大鼠肾脏生化指标及P-gp和OCT2蛋白表达水平，解释trelagliptin药代动力学变化的可能原因。结果：本研究表明，屈列列汀在高原低氧环境下的药动学参数发生了显著变化。与对照组比较，急慢性缺氧时AUC、MRT、t1/2、Vd均显著升高，CL、Ke均降低。P-gp和OCT2的生化指标及蛋白表达均发生显著变化。结论：研究表明，高原缺氧显著改变了trelagliptin的药代动力学，减缓了清除率，延长了消除半衰期和停留时间，提高了生物利用度。这些变化表明，在低氧暴露下，应重新评估trelagliptin的最佳治疗剂量。

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

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.