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BIOTRANSFORMATION OF FLUTICASONE: IN VITRO CHARACTERIZATION

Division of Pediatric Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics (R.E.P., J.S.L., G.L.K.), and Departments of Pediatrics (R.E.P., J.S.L., G.L.K.) and Pharmacology (J.S.L., G.L.K.), University of Missouri-Kansas City, Kansas City, Missouri

Fluticasone propionate (FTP) is a synthetic trifluorinated glucocorticoid with potent anti-inflammatory action that is commonly used in patients with asthma. After oral or intranasal administration, FTP undergoes rapid hepatic biotransformation; the principal metabolite formed is a 17ß-carboxylic acid derivative (M1). M1 formation has been attributed largely to cytochrome P450 3A4 (CYP3A4); however, there are no published data that confirm this assertion. Hence, in vitro studies were conducted to determine the role that human P450s play in the metabolism of FTP. Consistent with in vivo data, human liver microsomes catalyzed the formation of a single metabolite (M1) at substrate concentrations 10 µM (mean plasma C_max = 1 nM). Under these conditions, the kinetics of M1 formation in human liver microsomes were consistent with those of a single enzyme (K_m 5 µM). Formation of M1 correlated significantly (r > 0.95) with CYP3A4/5 activities in a panel of human liver microsomes (n = 14) and was markedly impaired by the CYP3A inhibitor ketoconazole (>94%) but not by inhibitors of other P450 enzymes (10%). Studies with a panel of cDNA-expressed enzymes revealed that M1 formation was catalyzed primarily by CYP3A enzymes at FTP concentrations 1 µM. M1 formation was catalyzed by P450s 3A4, 3A5, and 3A7; in vitro intrinsic clearance values (V_max/K_m) were comparable for all three CYP3A enzymes. These results suggest that at pharmacologically relevant concentrations, biotransformation of FTP to M1 is mediated predominantly by CYP3A enzymes in the liver.