Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Opp. Airforce Station, Palaj, Gandhinagar, 382355, Gujarat, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Opp. Airforce Station, Palaj, Gandhinagar, 382355, Gujarat, India.
Food Chem Toxicol. 2024 Aug;190:114785. doi: 10.1016/j.fct.2024.114785. Epub 2024 Jun 6.
In drug discovery, metabolite profiling unveils biotransformation pathways and potential toxicant formation, guiding selection of candidates with optimal pharmacokinetics and safety profiles. Tazemetostat (TAZ) is employed in treating locally advanced or metastatic epithelioid sarcoma. Identification of drug metabolites are of significant importance in improving safety, efficacy and reduced toxicity of drugs. The current study aimed to investigate the comprehensive metabolic fate of TAZ using different in vivo (rat) and in vitro (RLM, HLM, HS9) models. For in vivo studies, drug was orally administered to Sprague-Dawley rats with subsequent analysis of plasma, feces and urine samples. A total of 21 new metabolites were detected across various matrices and were separated on Phenomenex kinetex C18 (2.5 μm; 150 × 4.6 mm) column using acetonitrile and 0.1% formic acid in water as mobile phase. LC-QTOF-MS/MS and NMR techniques were employed to identify and characterize the metabolites from extracted samples. The major metabolic routes found in biotransformation of TAZ were hydroxylation, N-dealkylation, N-oxidation, hydrogenation, hydrolysis and N-acetylation. In silico toxicity revealed potential immunotoxicity for TAZ and few of its metabolites. This research article is the first time to discuss the complete metabolite profiling including identification and characterization of TAZ metabolites as well as its biotransformation mechanism.
在药物发现中，代谢物分析揭示了生物转化途径和潜在的毒物形成，指导选择具有最佳药代动力学和安全性特征的候选药物。他泽司他（TAZ）用于治疗局部晚期或转移性上皮样肉瘤。鉴定药物代谢物对于提高药物的安全性、疗效和降低毒性具有重要意义。本研究旨在使用不同的体内（大鼠）和体外（RLM、HLM、HS9）模型来研究 TAZ 的综合代谢命运。在体内研究中，将药物口服给予 Sprague-Dawley 大鼠，随后分析血浆、粪便和尿液样本。在各种基质中检测到 21 种新的代谢物，并使用 Phenomenex kinetex C18（2.5 μm；150×4.6 mm）柱，以乙腈和 0.1%甲酸的水溶液作为流动相进行分离。采用 LC-QTOF-MS/MS 和 NMR 技术从提取的样品中鉴定和表征代谢物。在 TAZ 的生物转化中发现的主要代谢途径是羟化、N-去烷基化、N-氧化、加氢、水解和 N-乙酰化。基于计算的毒性研究表明，TAZ 及其一些代谢物可能具有潜在的免疫毒性。本文首次讨论了 TAZ 代谢物的完整代谢物分析，包括鉴定和特征描述，以及其生物转化机制。
