Department of Bioanalysis and Drugs Analysis, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
Department of Cardiology, Postgraduate Medical School, Grochowski Hospital, 04-073 Warsaw, Poland.
Int J Mol Sci. 2020 Dec 18;21(24):9693. doi: 10.3390/ijms21249693.
Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.
安他唑啉（ANT）最近被证明是一种有效且安全的抗心律失常药物，可终止心房颤动。然而，该药物仍未列入临床指南。目前尚无关于人类 ANT 代谢的相关数据。我们使用液相色谱-串联质谱联用技术鉴定和分析了 ANT 甲磺酸盐在人体静脉注射 100mg 后的血浆以及人肝细胞体外培养物中的代谢产物。我们发现 ANT 至少转化为 15 种代谢产物，并研究了细胞色素 P450 同工酶的作用。CYP2D6 是参与 ANT 快速代谢的主要同工酶。CYP2C19 对 ANT 的生物转化作用要慢得多。主要的 I 相代谢物是 M1，由苯基的去除和苯基 位的羟基化形成，M2 是主要的代谢物。葡萄糖醛酸化是主要的 II 相代谢。进一步研究代谢产物的药代动力学可以帮助我们更好地了解 ANT 的活性特征，并预测其潜在的临床应用。最终，对 ANT 的新型羟基化 M2 代谢物的活性特征的进一步研究可能会产生一种与母体分子具有不同药理学特征的活性物质，并有潜力成为一种新的候选药物。
