DMD Noab BioDiscoveries - Shaping Drug Discovery

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on March 24, 2006; DOI: 10.1124/dmd.105.009043

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.009043v1
34/6/1035    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pearce, R. E.
Right arrow Articles by Kearns, G. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pearce, R. E.
Right arrow Articles by Kearns, G. L.


Received for publication December 20, 2005.
Revised March 21, 2006.
Accepted for publication March 21, 2006.

Biotransformation of Fluticasone: In Vitro Characterization

Robin E. Pearce 1, J. Steven Leeder 2, Gregory L. Kearns 2*

1 Children's Mercy Hospital & Clinics 2 Children's Mercy Hospital

* Address correspondence to: E-mail: gkearns{at}cmh.edu

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 to a single metabolite, a 17{beta}-carboxylic acid derivative (M1). M1 formation has been attributed largely to cytochrome P450 (CYP) 3A4, however, there are no published data that confirm this assertion. Hence, in vitro studies were conducted to determine the role that human cytochrome 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{approx}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 CYPs 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.


Key words: CYP3A, cytochrome P450 catalyzed oxidations, developmental pharmacology, human CYP enzymes, liver microsomes, mass spectrometry, steroids


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. C. Hughes, P. C. Shardlow, F. J. Hollis, R. J. Scott, D. S. Motivaras, A. Allen, and V. M. Rousell
Metabolism and Disposition of Fluticasone Furoate, an Enhanced-Affinity Glucocorticoid, in Humans
Drug Metab. Dispos., November 1, 2008; 36(11): 2337 - 2344.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.