Biotransformation of fluticasone: in vitro characterization.
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 17beta-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 <or=10 microM (mean plasma Cmax = 1 nM). Under these conditions, the kinetics of M1 formation in human liver microsomes were consistent with those of a single enzyme (Km congruent with 5 microM). 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 (<or=10%). Studies with a panel of cDNA-expressed enzymes revealed that M1 formation was catalyzed primarily by CYP3A enzymes at FTP concentrations <or=1 microM. M1 formation was catalyzed by P450s 3A4, 3A5, and 3A7; in vitro intrinsic clearance values (Vmax/Km) 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.
Division of Pediatric Clinical Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA.
Robin E
RE
Pearce
J Steven
JS
Leeder
Gregory L
GL
Kearns
D000730:Androstadienes / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068298:Fluticasone; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D015735:Mifepristone; D003577:Cytochrome P-450 Enzyme System; D000068298:Fluticasone; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole