In vitro inhibition and induction of human liver cytochrome P450 enzymes by a novel anti-fibrotic drug fluorofenidone

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.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.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.