Metabolism of IMM-H004 and Its Pharmacokinetic-Pharmacodynamic Analysis in Cerebral Ischemia/Reperfusion Injured Rats
Metabolism of IMM-H004 and Its Pharmacokinetic-Pharmacodynamic Analysis in Cerebral Ischemia/Reperfusion Injured Rats
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DOI：
10.3389/fphar.2019.00631
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发表时间：
2019-06
影响因子：
5.6
通讯作者：
Ziqian Zhang;Dan-dan Liu;Jianwei Jiang;Xiu-yun Song;Xiaowen Zou;Shi-Feng Chu;Kebo Xie;J. Dai
中科院分区：
文献类型：
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作者：
Ziqian Zhang;Dan-dan Liu;Jianwei Jiang;Xiu-yun Song;Xiaowen Zou;Shi-Feng Chu;Kebo Xie;J. Dai
IMM-H 004是一种香豆素衍生物，是一种很有前途的治疗脑缺血的药物。IMM-H 004的药效学机制仍在探索中。本研究从药物代谢的角度探讨IMM-H 004的药理活性物质。在大鼠体内发现了IMM-H 004的四种代谢物，包括脱甲基代谢物M1和M2、葡萄糖醛酸苷结合物IMM-H 004 G（M3）和硫酸化结合物M4。IMM-H 004 G是大鼠和培养的人肝细胞中的主要代谢产物，发现尿苷二磷酸-葡萄糖醛酸转移酶（UGT）在人肝微粒体（HLM）和大鼠肝微粒体（RLM）中催化IMM-H 004的代谢，具有高容量（Vmax为3.25和5.04 nmol/min/mg蛋白）。在13种重组人UGT亚型中，UGT 1A 7、1A 9、1A 8和1A 1似乎主要负责IMM-H 004 G的形成。IMM-H 004 G的暴露和持续时间（28，948 h × ng/ml的血药浓度-时间曲线下面积（AUC），t1/2β为6.61 h）远高于母体药物（AUC为1，638 h × ng/ml，t1/2β为0.42 h），与至少10 h的丙二醛（MDA）抑制作用一致。进一步的药理学研究表明IMM-H 004 G对缺氧缺糖损伤的PC 12细胞和短暂性MCAO/R损伤的大鼠均表现出与母体药物相似的神经保护活性。这些结果证明原型和IMM-H 004 G都是活性药物物质，并且IMM-H 004 G至少部分地有助于维持IMM-H 004的抗脑缺血功效。
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 hepatocytes, and uridine diphosphate-glucuronosyltransferase (UGT) was found to catalyze the metabolism of IMM-H004 in human liver microsomes (HLMs) and rat liver microsomes (RLMs) with high capacity (V max 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 (28,948 h × ng/ml of area under the plasma concentration–time curve (AUC), 6.61 h of t 1/2β) was much higher than that of the parent drug (1,638 h × ng/ml of AUC, 0.42 h of t 1/2β) in transient middle cerebral artery occlusion/reperfusion (MCAO/R) rats, consistent with the malondialdehyde (MDA) inhibition effect for at least 10 h. Further pharmacological study revealed that IMM-H004G exhibited a similar neuroprotective activity to that of the 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.