School of Xiangya Pharmaceutical Sciences, Central South University, Changsha, China.
The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China.
Xenobiotica. 2021 Jul;51(7):745-751. doi: 10.1080/00498254.2020.1820626. Epub 2021 May 18.
Fluorofenidone (AKF-PD) is an analog of pirfenidone and shows stronger antifibrotic effect and lower toxicity compared to pirfenidone in preclinical studies. However, the inhibitory and inducible effects of AKF-PD on human CYP450s are unclear. The aim of this study was to evaluate the ability of AKF-PD to inhibit and induce CYP450s .In inhibition study, the inhibitory effects of CYP1A2, CYP3A4, CYP2C9, CYP2E1, CYP2C19 and CYP2D6 by AKF-PD were evaluated with the metabolic rate of probe drug of each enzyme in pooled human liver microsomes. The enzyme inducible potential of AKF-PD was evaluated by the mRNA expression and enzyme activity of CYP1A2, CYP2B6 and CYP3A4 in human hepatocytes. The results suggested that AKF-PD produced weak inhibition on CYP1A2 and CYP2C19, while no inhibitory effects were found on the other enzymes. Since the plasma concentration of AKF-PD is much lower than the IC values of both CYP1A2 and CYP2C19, the inhibitory effects can be reasonably ignored.On the other hand, AKF-PD showed no inducible effects on CYP1A2 while showed potential inducible ability on CYP2B6 and CYP3A4 in some test groups. Further study of this novel anti-fibrotic drug should take into account in clinical therapies.
氟非尼酮（AKF-PD）是吡非尼酮的类似物，在临床前研究中与吡非尼酮相比，具有更强的抗纤维化作用和更低的毒性。然而，AKF-PD 对人细胞色素 P450（CYP450）的抑制和诱导作用尚不清楚。本研究旨在评估 AKF-PD 抑制和诱导 CYP450 的能力。在抑制研究中，用混合人肝微粒体中每种酶的探针药物的代谢率评估 AKF-PD 对 CYP1A2、CYP3A4、CYP2C9、CYP2E1、CYP2C19 和 CYP2D6 的抑制作用。通过人肝细胞中 CYP1A2、CYP2B6 和 CYP3A4 的 mRNA 表达和酶活性评估 AKF-PD 的酶诱导潜力。结果表明，AKF-PD 对 CYP1A2 和 CYP2C19 产生较弱的抑制作用，而对其他酶没有抑制作用。由于 AKF-PD 的血浆浓度远低于 CYP1A2 和 CYP2C19 的 IC 值，因此可以合理忽略其抑制作用。另一方面，AKF-PD 对 CYP1A2 没有诱导作用，而在某些实验组中对 CYP2B6 和 CYP3A4 具有潜在的诱导能力。在临床治疗中应考虑对这种新型抗纤维化药物的进一步研究。
