Dose proportionality and bioavailability of quinoxaline-based JNK inhibitor after single oral and intravenous administration in rats.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-01-01 Epub Date: 2024-01-02 DOI:10.1080/00498254.2023.2299686

Galina A Frelikh, Elena A Yanovskaya, Alexander P Lakeev, Galina A Chernysheva, Vera I Smolyakova, Anastasia R Kovrizhina

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Abstract

The dose proportionality and bioavailability of the potential anti-inflammatory and neuroprotective JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) were evaluated by comparing pharmacokinetic parameters after single oral (25, 50 and 100 mg/kg) and intravenous (1 mg/kg) IQ-1 administration in rats.IQ-1 and its major metabolite ketone 11H-indeno[1,2-b]quinoxalin-11-one (IQ-18) were isolated from plasma samples by liquid-liquid extraction. IQ-1 (E-isomer) and IQ-18 were simultaneously quantified in plasma by the validated method of liquid chromatography with triple quadrupole mass spectrometry (HPLC-MS/MS).The absolute bioavailability of IQ-1 was < 1.5%. C_max values were 24.72 ± 4.30, 25.66 ± 7.11 and 37.61 ± 3.53 ng/mL after single oral administration of IQ-1 at doses of 25, 50 and 100 mg/kg, respectively. IQ-1 exhibited dose proportionality at 50-100 mg/kg dose levels, whereas its pharmacokinetics was not dose proportional over the range of 25-50 mg/kg. IQ-18 demonstrated the invariance of the dose-normalized Cmax.In this study we systematically elucidated the absorption characteristics of IQ-1 in rat gastrointestinal tract and provided better understanding of IQ-1 pharmacology for the future development of a new formulations and therapeutic optimisation.

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基于喹喔啉的 JNK 抑制剂在大鼠口服和静脉注射后的剂量比例和生物利用度

1.通过比较大鼠单次口服（25、50 和 100 毫克/千克）和静脉注射（1 毫克/千克）IQ-1 后的药代动力学参数，评估了潜在的抗炎和神经保护性 JNK 抑制剂 11H-indeno[1,2-b]quinoxalin-11-one oxime（IQ-1）的剂量比例和生物利用度。通过液液萃取法从血浆样本中分离出 IQ-1 及其主要代谢物酮 11H-茚并[1,2-b]喹喔啉-11-酮（IQ-18）。采用液相色谱-三重四极杆质谱（HPLC-MS/MS）的有效方法同时对血浆中的 IQ-1（E-异构体）和 IQ-18 进行了定量。 IQ-1 的绝对生物利用度小于 1.5%。单次口服 25、50 和 100 毫克/千克剂量的 IQ-1 后，Cmax 值分别为 24.72 ± 4.30、25.66 ± 7.11 和 37.61 ± 3.53 纳克/毫升。在 50-100 毫克/千克的剂量水平上，IQ-1 的药代动力学呈剂量比例关系，而在 25-50 毫克/千克的剂量范围内，IQ-1 的药代动力学不呈剂量比例关系。本研究系统地阐明了 IQ-1 在大鼠胃肠道中的吸收特性，使我们对 IQ-1 的药理作用有了更好的了解，为今后开发新的制剂和优化治疗提供了依据。

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

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology