The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes

Abstract

The phase I metabolism of quinlukast (VÚFB 19363, Q; 4-{[4-(2-quinolylmethoxy)phenyl]- sulfanyl}benzoic acid), a new antiasthmatic drug with significant antileukotriene effects, was investigated in rat microsomes and hepatocytes. Quinlukast, incubated with rat liver microsomal fraction under oxidative conditions, generated four metabolites, M2-M5. Based on comparison with synthetically prepared standards, metabolites M2 and M4 were identified as sulfoxide and sulfone of the parent compound, respectively. Metabolites M3 and M5 were identified as quinlukast dihydrodiols. For all the metabolites the apparent kinetic parameters K'm, V'max and metabolic efficiency Clint were calculated. No metabolite was found in rat liver cytosol. In vitro studies with primary cultures of isolated hepatocytes were designed to evaluate time dependent (2, 4, 8 and 24 h) and concentration dependent (0.005-0.1 mmol/l) formation of metabolites of quinlukast. Four metabolites were detected in culture medium. Three of them were identical to metabolites found in incubation of quinlukast with microsomes (M2, M3 and M5) and another, the most polar metabolite, M1, was detected. The basic metabolic pathways were proposed for quinlukast in rats.