Pharmacokinetics, tissue distribution, plasma protein binding, and metabolism study of mefunidone, a novel pirfenidone derivative
Pharmacokinetics, tissue distribution, plasma protein binding, and metabolism study of mefunidone, a novel pirfenidone derivative
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新型吡非尼酮衍生物美夫尼酮的药代动力学、组织分布、血浆蛋白结合和代谢研究
DOI：
10.1111/1440-1681.13078
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发表时间：
2019-05-01
影响因子：
2.9
通讯作者：
Cheng, Zeneng
中科院分区：
文献类型：
--
作者：
Han, Xuhua;Li, Fang;Cheng, Zeneng
美福尼酮(MFD)是吡非尼酮(PFD)的新衍生物，具有良好的抗肾纤维化活性。为了避免临床第一阶段的早期开发失败和损耗，本研究对MFD的临床前药代动力学(PK)特性进行了评价。SD大鼠和食蟹猴分别以31.25 mg/kg和10 mg/kg的剂量灌胃和静脉给药，评价其绝对生物利用度。通过组织分布和血浆蛋白结合实验评价MFD的分布特征。利用人肝微粒体体外孵育系统，通过计算抑制率来检测参与MFD代谢的酶。在体外孵育系统和大鼠体内实验中，对MFD的代谢途径进行了研究。结果表明，MFD在体内吸收良好，在大鼠和猕猴体内的绝对生物利用度分别为77.2%和70.0%。MFD迅速分布于各组织，并高度集中在肾脏，肾脏是MFD的靶器官。大鼠、猴和人血浆蛋白结合率分别为36.40%~41.68%、30.88%~63.92%和37.75%~57.77%。MFD主要由细胞色素P450 3A4、细胞色素P450 2 C9和细胞色素P4 2 C8酶代谢。MFD的代谢途径是MFD核的吡啶环的氮脱甲基化、芳香环的羟基化和哌嗪环的脱甲基化。总之，在最初的临床前PK研究中，MFD表现出良好的PK特性。这些结果有力地支持了进一步的研究，以探索MFD作为临床抗肾纤维化药物的潜力。
Mefunidone (MFD), a novel derivation of pirfenidone (PFD), exhibits promising anti-renal fibrosis activity. To avoid early development failures and attrition in clinical phase 1, an evaluation of the preclinical pharmacokinetic (PK) properties of MFD was conducted in this study. The absolute bioavailability was evaluated in Sprague Dawley rats and cynomolgus monkeys, who received an intragastric or intravenous administration at the dose of 31.25 mg/kg and 10 mg/kg, respectively. Tissue distribution and plasma protein binding studies were performed to evaluate the distribution characteristics of MFD. The enzymes involved in the metabolism of MFD were assayed by calculating the inhibition rate using the in vitro incubation system of human liver microsomes. The metabolic pathway of MFD was also examined in the in vitro incubation system as well as in rats in vivo. The results revealed satisfactory absorption of MFD in vivo, with an absolute bioavailability of MFD in rats and monkeys of approximately 77.2% and 70.0%, respectively. MFD was rapidly distributed to all tissues and was highly concentrated in the kidney, which was the target organ of MFD. The plasma protein binding rates in rat, monkey, and human plasma were 36.40%-41.68%, 30.88%-63.92%, and 37.75%-57.77%, respectively. MFD was primarily metabolized by the enzymes CYP3A4, CYP2C9, and CYP2C8. The metabolic pathway of MFD is nitrogen demethylation of the pyridine ring of the MFD nucleus, hydroxylation of the aromatic ring, and demethylation of the piperazine ring. In conclusion, MFD exhibited good PK properties in the initial preclinical PK study. The results strongly support further research to investigate the potential of MFD as a clinical anti-renal fibrosis drug.