Yu Lu, Chen Xu, Zhang Wen Sheng, Zheng Liang, Xu Wen Wen, Xu Ming Yu, Jiang Xue Hua, Wang Ling
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University, Chengdu 610064, People's Republic of China.
Chengdu Women and Children Central Hospital, Chengdu, Sichuan 610041, People's Republic of China.
R Soc Open Sci. 2020 Feb 12;7(2):191666. doi: 10.1098/rsos.191666. eCollection 2020 Feb.
ET-26-HCl, a novel anaesthetic agent with promising pharmacological properties, lacks extensive studies on pharmacokinetics and disposition and . In this study, we investigated the metabolic stability, metabolite production and plasma protein binding (PPB) of ET-26-HCl along with its tissue distribution, excretion and pharmacokinetics in animals after intravenous administration. Ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry identified a total of eight new metabolites after ET-26-HCl biotransformation in liver microsomes from different species. A hypothetical cytochrome P450-metabolic pathway including dehydrogenation, hydroxylation and demethylation was proposed. The PPB rate was highest in mouse and lowest in human. After intravenous administration, ET-26-HCl distributed rapidly to all tissues in rats and beagle dogs, with the highest concentrations in fat and liver. High concentrations of ET-26-acid, a major hydroxylation metabolite of ET-26-HCl, were found in liver, plasma and kidney. Almost complete clearance of ET-26-HCl from plasma occurred within 4 h after administration. Only a small fraction of the parent compound and its acid form were excreted via the urine and faeces. Taken together, the results added to a better understanding of the metabolic and pharmacokinetic properties of ET-26-HCl, which may contribute to the further development of this drug.
ET-26-HCl是一种具有良好药理特性的新型麻醉剂，但缺乏关于其药代动力学和处置的广泛研究。在本研究中，我们研究了ET-26-HCl的代谢稳定性、代谢产物生成和血浆蛋白结合（PPB），以及静脉给药后其在动物体内的组织分布、排泄和药代动力学。超高效液相色谱-串联四极杆飞行时间质谱法在不同物种肝脏微粒体中ET-26-HCl生物转化后共鉴定出8种新的代谢产物。提出了一种包括脱氢、羟基化和去甲基化的假设性细胞色素P450代谢途径。PPB率在小鼠中最高，在人类中最低。静脉给药后，ET-26-HCl在大鼠和比格犬体内迅速分布到所有组织，脂肪和肝脏中的浓度最高。在肝脏、血浆和肾脏中发现了高浓度的ET-26-酸，它是ET-26-HCl的主要羟基化代谢产物。给药后4小时内，ET-26-HCl几乎完全从血浆中清除。只有一小部分母体化合物及其酸形式通过尿液和粪便排泄。综上所述，这些结果有助于更好地理解ET-26-HCl的代谢和药代动力学特性，这可能有助于该药物的进一步开发。
