Abstract
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 17β-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 Cmax = 1 nM). Under these conditions, the kinetics of M1 formation in human liver microsomes were consistent with those of a single enzyme (Km ≅ 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 (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.
Footnotes
-
This work was supported in part by grants from the Pediatric Pharmacology Research Unit Network (2 U01 HD031313-12; to G.L.K.) and Pediatric Adverse Drug Reaction Network (1 U01 HD044239-2; to J.S.L.), National Institute of Child Health and Human Development, Bethesda, MD, and by a grant from the Katherine Berry Richardson Foundation, Children's Mercy Hospital, Kansas City, MO (to R.E.P.).
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.105.009043.
-
ABBREVIATIONS: FTP, fluticasone propionate; P450, cytochrome P450; HPLC, high-performance liquid chromatography; MS, mass spectrometry; fluticasone, 6α,9α-difluoro-11β-hydroxy-17α-(propionyloxy)-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate; fluticasone 17β-carboxylic acid (M1), 6α,9α-difluoro-11β-hydroxy-17α-(propionyloxy)-16α-methyl-3-oxoandrosta-1, 4-diene-17β-carboxylic acid; ketoconazole, cis-1-acetyl-4-[4[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine; α-naphthoflavone, 7,8-benzoflavone; mifepristone, 11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one; omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimadazole; quinidine, dextro-6′-methoxycinchonan-9-ol; sulfaphenazole, 4-amino-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide; ticlopidine, 5-(o-chlorobenzyl)-4,5,6,7-tetrahydrothieno(3,2-c)pyridine.
- Received December 20, 2005.
- Accepted March 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|