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
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.
MetabolitesBiochemistry, 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.