![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 29, Issue 7, 1029-1034, July 2001
Department of Basic Pharmaceutical Sciences, School of Pharmacy,
West Virginia University, Morgantown, West Virginia (J.M.H., T.S.T.);
and Pharmacia, Inc. Global Metabolism and Investigative Sciences,
Kalamazoo, Michigan (M.J.H.)
Dapsone activates CYP2C9-mediated metabolism in various expression
systems and is itself metabolized by CYP2C9 to its hydroxylamine metabolite. Studies were conducted with expressed CYP2C9 to
characterize the kinetic effects of dapsone (0-100 µM) on
(S)-flurbiprofen (2-300 µM),
(S)-naproxen (10-1800 µM), and piroxicam (5-900
µM) metabolism in 6 × 6 matrix design experiments. The
influence of (S)-flurbiprofen on dapsone hydroxylamine
formation was also studied. Dapsone increased the
Michaelis-Menten-derived Vmax of
flurbiprofen 4'-hydroxylation from 12.6 to 20.6 pmol/min/pmol P450, and
lowered its Km from 28.9 to 10.0 µM,
suggesting that dapsone activates CYP2C9-mediated flurbiprofen
metabolism without displacing flurbiprofen from the active site,
supporting a two-site model describing activation. Similar results were
observed with piroxicam 5'-hydroxylation, as
Vmax was increased from 0.08 to 0.20 pmol/min/pmol P450 and Km was decreased from
183 to 50 µM in the presence of dapsone. In addition, the kinetic
profile for naproxen was converted from biphasic to hyperbolic in the
presence of dapsone, while exhibiting similar decreases in
Km and increases in
Vmax. Kinetic parameters were also estimated
using the two-site binding equation, with 
values <1 and 
values
>1, indicative of activation. Additionally, dapsone hydroxylamine
formation was measured from incubations containing flurbiprofen,
exhibiting a kinetic profile that was minimally affected by the
presence of flurbiprofen. Overall, these results suggest that dapsone
activates the metabolism of multiple substrates of CYP2C9 by binding
within the active site and causing positive cooperativity, thus lending
further support to a two-site binding model of P450-mediated metabolism.
This article has been cited by other articles:
|
|
 |
|
  D. Si, Y. Wang, Y.-H. Zhou, Y. Guo, J. Wang, H. Zhou, Z.-S. Li, and J. P. Fawcett Mechanism of CYP2C9 Inhibition by Flavones and Flavonols Drug Metab. Dispos., March 1, 2009; 37(3): 629 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mast, M. A. White, I. Bjorkhem, E. F. Johnson, C. D. Stout, and I. A. Pikuleva Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain PNAS, July 15, 2008; 105(28): 9546 - 9551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ghosal, R. Ramanathan, Y. Yuan, N. Hapangama, S. K. Chowdhury, N. S. Kishnani, and K. B. Alton Identification of Human Liver Cytochrome P450 Enzymes Involved in Biotransformation of Vicriviroc, a CCR5 Receptor Antagonist Drug Metab. Dispos., December 1, 2007; 35(12): 2186 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Isin and F. P. Guengerich Multiple Sequential Steps Involved in the Binding of Inhibitors to Cytochrome P450 3A4 J. Biol. Chem., March 2, 2007; 282(9): 6863 - 6874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Kumar, J. L. Wahlstrom, D. A. Rock, C. J. Warren, L. A. Gorman, and T. S. Tracy CYP2C9 Inhibition: Impact of Probe Selection and Pharmacogenetics on in Vitro Inhibition Profiles Drug Metab. Dispos., December 1, 2006; 34(12): 1966 - 1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Isin and F. P. Guengerich Kinetics and Thermodynamics of Ligand Binding by Cytochrome P450 3A4 J. Biol. Chem., April 7, 2006; 281(14): 9127 - 9136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. McGinnity, J. Tucker, S. Trigg, and R. J. Riley PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES Drug Metab. Dispos., November 1, 2005; 33(11): 1700 - 1707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Hummel, C. W. Locuson, P. M. Gannett, D. A. Rock, C. M. Mosher, A. E. Rettie, and T. S. Tracy CYP2C9 Genotype-Dependent Effects on in Vitro Drug-Drug Interactions: Switching of Benzbromarone Effect from Inhibition to Activation in the CYP2C9.3 Variant Mol. Pharmacol., September 1, 2005; 68(3): 644 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-C. Egnell, J. B. Houston, and C. S. Boyer Predictive Models of CYP3A4 Heteroactivation: In Vitro-in Vivo Scaling and Pharmacophore Modeling J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 926 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-H. Liu, M.-J. Kim, W. M. Jung, W. Kang, I.-J. Cha, and J.-G. Shin LANSOPRAZOLE ENANTIOMER ACTIVATES HUMAN LIVER MICROSOMAL CYP2C9 CATALYTIC ACTIVITY IN A STEREOSPECIFIC AND SUBSTRATE-SPECIFIC MANNER Drug Metab. Dispos., February 1, 2005; 33(2): 209 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Wester, J. K. Yano, G. A. Schoch, C. Yang, K. J. Griffin, C. D. Stout, and E. F. Johnson The Structure of Human Cytochrome P450 2C9 Complexed with Flurbiprofen at 2.0-A Resolution J. Biol. Chem., August 20, 2004; 279(34): 35630 - 35637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-C. Egnell, C. Eriksson, N. Albertson, B. Houston, and S. Boyer Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 878 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Galetin, S. E. Clarke, and J. B. Houston MULTISITE KINETIC ANALYSIS OF INTERACTIONS BETWEEN PROTOTYPICAL CYP3A4 SUBGROUP SUBSTRATES: MIDAZOLAM, TESTOSTERONE, AND NIFEDIPINE Drug Metab. Dispos., September 1, 2003; 31(9): 1108 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hutzler and T. S. Tracy Atypical Kinetic Profiles in Drug Metabolism Reactions Drug Metab. Dispos., April 1, 2002; 30(4): 355 - 362. [Full Text] [PDF]
|
|
|
|
|
|
T. S. Tracy, J. M. Hutzler, R. L. Haining, A. E. Rettie, M. A. Hummel, and L. J. Dickmann Polymorphic Variants (CYP2C9*3 and CYP2C9*5) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles Drug Metab. Dispos., April 1, 2002; 30(4): 385 - 390. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
