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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00631

Metabolism of IMM-H004 and its pharmacokinetic-pharmacodynamic analysis in cerebral ischemia/reperfusion injured rats

 Ziqian Zhang1, Dandan Liu2, Jianwei Jiang2,  Xiuyun Song2, Xiaowen Zou2, Shifeng Chu2, Jungui Dai2,  Li Sheng2*,  Nai-Hong Chen2* and Yan Li2
  • 1Chinese Academy of Medical Sciences, China
  • 2Institute of Materia Medica (IMM), China

IMM-H004, a derivative of coumarin, is a promising candidate for the treatment of cerebral ischemia. The pharmacodynamic mechanisms of IMM-H004 are still under exploration. The present study was conducted to explore the pharmacoactive substances of IMM-H004 from the perspective of drug metabolism. Four metabolites of IMM-H004 including demethylated metabolites M1 and M2, glucuronide conjugate IMM-H004G (M3) and sulfated conjugate M4 were found in rats in vivo. IMM-H004G was the major metabolite in rats and cultured human hepatocyte, and UDP-glucuronosyltransferase (UGTs) were found to catalyze the metabolism of IMM-H004 in human liver microsomes (HLMs) and rat liver microsomes (RLMs) with high capacity (Vmax at 3.25 and 5.04 nmol/min/mg protein). Among 13 recombinant human UGT isoforms, UGT1A7, 1A9, 1A8 and 1A1 appeared to be primarily responsible for IMM-H004G formation. The exposure and duration of IMM-H004G (28948 h×ng/mL of AUC, 6.61 h of t1/2β) was much higher than that of the parent drug (1638 h×ng/mL of AUC, 0.42 h of t1/2β) in transient middle cerebral artery occlusion/ reperfusion (MCAO/R) rats, consistent with the malondialdehyde inhibition effect for at least 10 h. Further pharmacological study revealed that IMM-H004G exhibited a similar neuroprotective activity to that of parent drug on both oxygen-glucose deprivation injured PC12 cells and transient MCAO/R injured rats. These results demonstrate that both prototype and IMM-H004G are the active pharmaceutical substances, and IMM-H004G, at least in part, contributes to the maintenance of anti-cerebral ischemia efficacy of IMM-H004.

Keywords: drug metabolism, PK/PD, UGTs, UDP-glucuronosyltransferases, CYPs, cytochrome P450 enzymes, cerebral ischemia, Neuroprotection, IMM-H004

Received: 03 Mar 2019; Accepted: 17 May 2019.

Edited by:

Miia Turpeinen, University of Oulu, Finland

Reviewed by:

Stanislav Yanev, Institute of Neurobiology (BAS), Bulgaria
Dong Hyun Kim, Inje University College of Medicine, South Korea  

Copyright: © 2019 Zhang, Liu, Jiang, Song, Zou, Chu, Dai, Sheng, Chen and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Li Sheng, Institute of Materia Medica (IMM), Beijing, 100050, Beijing Municipality, China, shengli@imm.ac.cn
Dr. Nai-Hong Chen, Institute of Materia Medica (IMM), Beijing, 100050, Beijing Municipality, China, chennh@imm.ac.cn