The Comparative Metabolism of a Novel Hepatocellular Carcinoma Therapeutic Agent, 2,3-Diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide, in Human and Animal Hepatocytes

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Metabolites Pub Date : 2024-08-01 DOI:10.3390/metabo14080425

Young-Heun Jung, Dong-Cheol Lee, Ye-Min Kwon, Eunbee Jang, Garam Choi, Yeoun-Hee Kim, Tae Hwan Kim, Ju-Hyun Kim

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引用次数: 0

Abstract

[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography–high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.

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新型肝细胞癌治疗剂 2,3-二氨基-N-(4-(苯并[d]噻唑-2-基)苯基)丙酰胺在人类和动物肝细胞中的代谢比较

被命名为 ETN101 的[2,3-二氨基-N-(4-(苯并[d]噻唑-2-基)苯基)丙酰胺]是一种治疗肝细胞癌的新型药物。体外研究检测了 ETN101 在人、小鼠、大鼠、狗和猴子肝细胞中的代谢物，并使用 cDNA 表达的重组人细胞色素 P450s（CYPs）、羧基酯酶（CESs）、N-乙酰转移酶（NAT）1 和人肝细胞溶液鉴定了所涉及的药物代谢酶。ETN101 在五个物种的肝细胞中表现出相似的代谢稳定性，尤其是在人类、大鼠和猴子体内的稳定性相当。它在人体内的半衰期为 75.0 分钟，在大鼠体内为 68.9 分钟，在猴子体内为 73.1 分钟，在小鼠体内为 120.4 分钟，在狗体内为 112.7 分钟。使用液相色谱-高分辨质谱法鉴定了 34 种 ETN101 代谢物，包括主要代谢物 M1。ETN101 主要代谢为 M1，CYP1A2 专门负责 M1 的代谢。NAT1 和 NAT2 负责 M1 到 M2 的 N-乙酰化。ETN101 在人体 CES 中保持稳定。总之，本研究全面揭示了 ETN101 的代谢特征，对其毒理学和临床开发具有重要价值。

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

Metabolites Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

5.70

自引率

7.30%

发文量

1070

审稿时长

17.17 days

期刊介绍： Metabolites (ISSN 2218-1989) is an international, peer-reviewed open access journal of metabolism and metabolomics. Metabolites publishes original research articles and review articles in all molecular aspects of metabolism relevant to the fields of metabolomics, metabolic biochemistry, computational and systems biology, biotechnology and medicine, with a particular focus on the biological roles of metabolites and small molecule biomarkers. Metabolites encourages scientists to publish their experimental and theoretical results in as much detail as possible. Therefore, there is no restriction on article length. Sufficient experimental details must be provided to enable the results to be accurately reproduced. Electronic material representing additional figures, materials and methods explanation, or supporting results and evidence can be submitted with the main manuscript as supplementary material.