Abstract

1. 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 vitro.

2. 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 IC₅₀ values of both CYP1A2 and CYP2C19, the inhibitory effects can be reasonably ignored.

3. 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.

摘要

1. 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显示出更强的抗纤维化作用和更低的毒性。然而，AKF-PD 对人 CYP450 的抑制和诱导作用尚不清楚。本研究的目的是评估 AKF-PD在体外抑制和诱导 CYP450 的能力。

2. 在抑制研究中，AKF-PD对CYP1A2、CYP3A4、CYP2C9、CYP2E1、CYP2C19和CYP2D6的抑制作用是通过混合的人肝微粒体中各酶的探针药物代谢率来评价的。AKF-PD的酶诱导潜能通过CYP1A2、CYP2B6和CYP3A4在人肝细胞中的mRNA表达和酶活性进行评估。结果表明，AKF-PD对CYP1A2和CYP2C19的抑制作用较弱，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 ₅₀值，因此可以合理地忽略抑制作用。

3. 另一方面，AKF-PD 对 CYP1A2 没有诱导作用，而在一些测试组中对 CYP2B6 和 CYP3A4 显示出潜在的诱导能力。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。