Characterization of enzymes responsible for biotransformation of the new antileukotrienic drug quinlukast in rat liver microsomes and in primary cultures of rat hepatocytes.

The promising new drug quinlukast, 4-(4-(quinoline-2′-yl-methoxy)phenylsulphanyl)benzoic acid (VUFB 19363), is under investigation for its anti-inflammatory and anti-asthmatic effects. The main metabolite of quinlukast identified in incubations of rat microsomal fraction, and in primary culture of rat hepatocytes, is quinlukast sulfoxide (M2). Also, several other metabolites of quinlukast were found: two dihydrodiol derivatives (M3, M5) and quinlukast sulfone (M4). This study was conducted to characterize the enzymes involved in quinlukast biotransformation in rat in-vitro. Primary cultures of rat hepatocytes were treated with inducers of different cytochrome P450s (CYPs) for 48 h. Quinlukast (100 μm) was incubated for 24 h in a primary culture of induced or control hepatocytes. The effects of CYP inhibitors, ketoconazole, methylpyrazole, metyrapone and α-naphthoflavone (2, 10, 50 μm), on quinlukast metabolism were tested in induced and control hepatocytes. Significant induction of M2 (6 times), M5 (twice) and M3 (by 50%) formation by dexamethasone and strong concentration-dependent inhibition by ketoconazole indicated that CYP3A participates in formation of these metabolites. CYP1A catalyses formation of metabolite M3 mainly, as β-naphthoflavone induced (10 times) production of M3 and a strong inhibitory effect of α-naphthoflavone on its formation was observed. A significant inhibitory effect of quinlukast (2, 10, 50 μm) on ethoxyresorufin, methoxyresorufin and benzyloxyresorufin O-dealkylase activity was observed as well.