Chen Junqi, Wang Ziteng, Yong Ching Yee, Goh Evelyn Mei Ling, Moy Hooi Yan, Chan Eric Chun Yong
Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
Analytical Toxicology Laboratory, Applied Sciences Group, Health Sciences Authority, 11 Outram Road, Singapore, 169078, Singapore.
Arch Toxicol. 2025 Mar;99(3):1085-1094. doi: 10.1007/s00204-024-03952-7. Epub 2025 Jan 3.
Psilocin is a well-studied controlled substance with potential psychotherapeutic applications. However, research gaps remain regarding its metabolism. Our objective was to elucidate a comprehensive Phase I metabolic profile of psilocin to support its forensic management and clinical development. We utilized human enzymes from various sources to characterize the Phase I metabolism of psilocin and estimated its hepatic and extrahepatic clearances via in vitro to in vivo extrapolation. We identified 2-(4-hydroxy-1H-indol-3-yl)-acetaldehyde (4-HIA) as the Phase I intermediate metabolite for the first time. Psilocin was metabolized to 4-HIA by monoamine oxidase A (MAO-A), and further metabolized to the terminal metabolite 2-(4-hydroxy-1H-indol-3-yl)-acetic acid (4-HIAA) by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs). MAO-A-mediated hepatic clearance of psilocin (CL) was estimated to be 158.74 mL/min, accounting for 80.9% of the total hepatic metabolism of psilocin (CL). MAO-A primarily contributed to the Phase I metabolism of psilocin. Total MAO-A-mediated organ clearance (CL) was estimated to be 614.81 mL/min, with CL accounting for 25.8%, indicating extensive MAO-A-mediated extrahepatic clearance of psilocin. Overall, our study sheds novel insights on Phase I metabolic pathway of psilocin and illuminated the importance of MAO-A-mediated hepatic and extrahepatic clearances of psilocin.
裸盖菇素是一种经过充分研究的受管制物质，具有潜在的心理治疗应用价值。然而，关于其代谢仍存在研究空白。我们的目标是阐明裸盖菇素全面的I期代谢概况，以支持其法医学管理和临床开发。我们利用来自各种来源的人类酶来表征裸盖菇素的I期代谢，并通过体外到体内的外推法估计其肝脏和肝外清除率。我们首次确定2-(4-羟基-1H-吲哚-3-基)乙醛（4-HIA）为I期中间代谢产物。裸盖菇素被单胺氧化酶A（MAO-A）代谢为4-HIA，并进一步被胞质醛氧化酶（AO）和醛脱氢酶（ALDHs）代谢为终末代谢产物2-(4-羟基-1H-吲哚-3-基)乙酸（4-HIAA）。MAO-A介导的裸盖菇素肝脏清除率（CL）估计为158.74 mL/min，占裸盖菇素总肝脏代谢（CL）的80.9%。MAO-A对裸盖菇素的I期代谢起主要作用。MAO-A介导的总器官清除率（CL）估计为614.81 mL/min，其中CL占25.8%，表明MAO-A介导的裸盖菇素肝外清除广泛。总体而言，我们的研究为裸盖菇素的I期代谢途径提供了新的见解，并阐明了MAO-A介导的裸盖菇素肝脏和肝外清除的重要性。
