Füll Yvonne, Wallasch Christian, Hilton Ashley, Planz Oliver
Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.
Atriva Therapeutics GmbH, Tuebingen, Germany.
Front Pharmacol. 2022 Dec 5;13:1050193. doi: 10.3389/fphar.2022.1050193. eCollection 2022.
Zapnometinib is a MEK inhibitor currently under clinical development for the treatment of COVID-19 and influenza. Zapnometinib has both antiviral and immunomodulatory effects. Information concerning the absorption, distribution, metabolism, and excretion of the compound following single oral doses of 30 mg/kg [C]-zapnometinib to rats was required to support pharmacology and toxicology studies in animals and clinical studies in man. As part of the development and safety assessment of this substance, zapnometinib was radioactively labeled and used for the investigation of time-dependent plasma concentrations, the rates and routes of excretion, the extent and time-course of compound distribution in body tissues, the metabolite profiles in plasma, urine and feces and the chemical nature of its metabolites. The present study reveals a rapid but low absorption of zapnometinib from the gastrointestinal tract, with more than 90% of the compound being excreted within 48 h, mainly feces. Whole body autoradiography confirms that zapnometinib was rapidly and widely distributed, with greatest concentrations in the circulatory and visceral tissues. Maximum plasma and tissue concentrations occurred between two and 8 h post dose. Penetration into the brain was low, and elimination from most tissues almost complete after 168 h. Metabolic profiles showed that the main clearance routes were metabolism oxidative reactions and glucuronidation. These results further strengthen the knowledge of zapnometinib with respect to the clinical development of the drug.
扎普诺美替尼是一种MEK抑制剂，目前正处于治疗新冠肺炎和流感的临床开发阶段。扎普诺美替尼具有抗病毒和免疫调节作用。为支持动物药理学和毒理学研究以及人体临床研究，需要有关大鼠单次口服30mg/kg [C] -扎普诺美替尼后该化合物的吸收、分布、代谢和排泄信息。作为该物质开发和安全性评估的一部分，扎普诺美替尼被放射性标记，并用于研究时间依赖性血浆浓度、排泄速率和途径、化合物在身体组织中的分布程度和时间进程、血浆、尿液和粪便中的代谢物谱以及其代谢物的化学性质。本研究表明扎普诺美替尼从胃肠道吸收迅速但程度较低，超过90%的化合物在48小时内排泄，主要通过粪便。全身放射自显影证实扎普诺美替尼分布迅速且广泛，在循环和内脏组织中浓度最高。给药后2至8小时出现最大血浆和组织浓度。进入大脑的渗透率较低，168小时后大多数组织中的消除几乎完成。代谢谱显示主要清除途径是氧化反应和葡萄糖醛酸化代谢。这些结果进一步加强了关于扎普诺美替尼药物临床开发的知识。
