"Branched Tail" Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip.

Drug metabolism letters Pub Date : 2019-01-01 DOI:10.2174/1872312813666181129100950

Andrey A Poloznikov, Sergey V Nikulin, Arpenik A Zakhariants, Anna Y Khristichenko, Dmitry M Hushpulian, Ildar N Gazizov, Vladimir I Tishkov, Irina G Gazaryan

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引用次数: 6

Abstract

Background: "Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection.

Objective: The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs.

Method: Liver-on-a-chip technology with differentiated HepaRG cells followed by LC-MS detection of the studied compounds and metabolites of the P450 substrate-inhibitor panel for CYP2B6, CYP2C9, CYP2C19, and CYP3A4.

Results: The optimized adaptaquin analogs show no toxicity up to a 100-fold increased range over EC50. The drugs are metabolized by CYP3A4 and CYP2B6 as shown with the use of the cytochrome P450 substrate-inhibitor panel designed and optimized for preclinical evaluation of drugs' in vitro biotransformation on a 3D human histotypical cell model using "liver-on-a-chip" technology. Activation of CYP2B6 with the drugs tested has been observed. A scheme for adaptaquin oxidative conversion is proposed.

Conclusion: The optimized adaptaquin analogs are suitable for further preclinical trials. Activation of CYP2B6 with adaptaquin and its variants points to a potential increase in Tylenol toxicity if administered together.

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HIF脯氨酸羟化酶的“支尾”氧喹啉抑制剂:使用肝脏芯片对毒性和代谢的早期评估。

背景:支尾氧喹啉类药物，尤其是adaptaquin，是一种有效的HIF脯氨酰羟化酶抑制剂，在体内出血性卒中模型中显示出良好的效果。效价的进一步提高导致鉴定出许多适应喹啉类似物。在选择铅的步骤中，需要对毒性和代谢进行早期评估。目的:研究适应他喹及其新改良类似物的毒性和代谢特性。方法:采用肝芯片技术与分化的HepaRG细胞结合，采用LC-MS检测所研究的CYP2B6、CYP2C9、CYP2C19和CYP3A4的P450底物抑制剂面板的化合物和代谢物。结果:优化后的adaptaquin类似物在EC50以上增加100倍的范围内无毒性。药物通过CYP3A4和CYP2B6代谢，如图所示，使用细胞色素P450底物-抑制剂面板设计和优化，用于临床前评估药物在3D人组织典型细胞模型上的体外生物转化，使用“肝脏芯片”技术。已观察到CYP2B6与所测试药物的激活。提出了一种自适应喹啉氧化转化方案。结论:优化后的自适应喹啉类似物可用于进一步的临床前试验。CYP2B6与adaptaquin及其变体的激活表明，如果一起给药，泰诺的毒性可能会增加。

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

Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.