JPET Celsis microsomes equal better data

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


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
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
Right arrow Citation Map
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 Ludwig, E.
Right arrow Articles by Ebner, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ludwig, E.
Right arrow Articles by Ebner, T.

Vol. 290, Issue 1, 1-8, July 1999

Activation of Human Cytochrome P-450 3A4-Catalyzed Meloxicam 5'-Methylhydroxylation by Quinidine and Hydroquinidine In Vitro

Eva Ludwig, Jochen Schmid, Klaus Beschke and Thomas Ebner

Department of Pharmacokinetics and Drug Metabolism, Boehringer Ingelheim Pharma KG, Biberach an der Riss, Germany

In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased Km and increased Vmax of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both Km and Vmax of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations.

0022-3565/99/2901-0001$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
C. Lu, G. T. Miwa, S. R. Prakash, L.-S. Gan, and S. K. Balani
A Novel Model for the Prediction of Drug-Drug Interactions in Humans Based on in Vitro Cytochrome P450 Phenotypic Data
Drug Metab. Dispos., January 1, 2007; 35(1): 79 - 85.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Drug Metab. Dispos.Home page
L. Shen, J. F. Fitzloff, and C. S. Cook
DIFFERENTIAL ENANTIOSELECTIVITY AND PRODUCT-DEPENDENT ACTIVATION AND INHIBITION IN METABOLISM OF VERAPAMIL BY HUMAN CYP3AS
Drug Metab. Dispos., February 1, 2004; 32(2): 186 - 196.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Drug Metab. Dispos.Home page
G. B. J. Smith, J. R. Bend, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey
BIOTRANSFORMATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK) IN PERIPHERAL HUMAN LUNG MICROSOMES
Drug Metab. Dispos., September 1, 2003; 31(9): 1134 - 1141.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Galetin, S. E. Clarke, and J. B. Houston
Quinidine and Haloperidol as Modifiers of CYP3A4 Activity: Multisite Kinetic Model Approach
Drug Metab. Dispos., December 1, 2002; 30(12): 1512 - 1522.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
Y. Masubuchi, A. Ose, and T. Horie
Diclofenac-Induced Inactivation of CYP3A4 and Its Stimulation by Quinidine
Drug Metab. Dispos., October 1, 2002; 30(10): 1143 - 1148.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Drug Metab. Dispos.Home page
K. E. Kenworthy, S. E. Clarke, J. Andrews, and J. B. Houston
Multisite Kinetic Models for CYP3A4: Simultaneous Activation and Inhibition of Diazepam and Testosterone Metabolism
Drug Metab. Dispos., December 1, 2001; 29(12): 1644 - 1651.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. S. Ngui, Q. Chen, M. Shou, R. W. Wang, R. A. Stearns, T. A. Baillie, and W. Tang
In Vitro Stimulation of Warfarin Metabolism by Quinidine: Increases in the Formation of 4'- and 10-Hydroxywarfarin
Drug Metab. Dispos., June 1, 2001; 29(6): 877 - 886.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. L. Domanski, Y.-A. He, G. R. Harlow, and J. R. Halpert
Dual Role of Human Cytochrome P450 3A4 Residue Phe-304 in Substrate Specificity and Cooperativity
J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 585 - 591.
[Abstract] [Full Text]


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

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.