Collect. Czech. Chem. Commun. 2004, 69, 689-702

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

Vladimír Wsóla,b,*, Barbora Szotákováa,b, Vendula Baliharováb, Luděk Šišperab, Michal Holčapekc, Lenka Kolářovác, Bohumila Suchanováb, Miroslav Kuchařd and Lenka Skálováa,b

a Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
b Research Centre LN00B125, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
c Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, nám. Čs. legií 565, 532 10 Pardubice, Czech Republic
d Research Institute for Pharmacy and Biochemistry, U Kabelovny 130, 102 37 Prague 10, Czech Republic


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.

Keywords: Antiasthmatics; Drug metabolism; Metabolic pathways; Hepatocytes; Microsomes; Enzyme kinetics; Kinetic parameters; LC-MS; Biotransformations; Antihistaminics; Metabolites.

References: 17 live references.