DMD

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


     

Drug Metabolism and Disposition Fast Forward
First published on October 3, 2007; DOI: 10.1124/dmd.107.018010

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.107.018010v1
36/1/73    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 Tornio, A.
Right arrow Articles by Backman, J. T
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tornio, A.
Right arrow Articles by Backman, J. T


Received for publication August 1, 2007.
Revised September 13, 2007.
Accepted for publication October 2, 2007.

Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone

Aleksi Tornio 1, Mikko Niemi 1, Pertti J Neuvonen 1, Janne T Backman 1*

1 University of Helsinki

* Address correspondence to: E-mail: janne.backman{at}helsinki.fi

Abstract

We studied the effects of the CYP2C8 inhibitor trimethoprim and CYP2C8 genotype on the pharmacokinetics of the antidiabetic pioglitazone. In a randomized crossover study, 16 healthy volunteers with the CYP2C8*1/*1 (n=8), *1/*3 (n=5), or *3/*3 (n=3) genotype ingested 160 mg trimethoprim or placebo twice daily for 6 days. On day 3, they ingested 15 mg pioglitazone. In vitro, the effects of trimethoprim on pioglitazone were characterized. Trimethoprim raised the area under the plasma pioglitazone concentration-time curve (AUC0-{infty}) by 42% (p < 0.001), and decreased the formation rates of pioglitazone metabolites M-IV and M-III (p < 0.001). During the placebo phase, the weight-adjusted AUC0-{infty} of pioglitazone was 34% smaller in the CYP2C8*3/*3 and 26% smaller in the CYP2C8*1/*3 than in the CYP2C8*1/*1 group (p < 0.05). In vitro, trimethoprim inhibited M-IV formation (inhibition constant 38.2 µM), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.


Key words: CYP2C, drug interactions, pharmacogenetics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S.-Y. Chang, W. Li, S. C. Traeger, B. Wang, D. Cui, H. Zhang, B. Wen, and A. D. Rodrigues
Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro
Drug Metab. Dispos., December 1, 2008; 36(12): 2513 - 2522.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. A. Schoch, J. K. Yano, S. Sansen, P. M. Dansette, C. D. Stout, and E. F. Johnson
Determinants of Cytochrome P450 2C8 Substrate Binding: STRUCTURES OF COMPLEXES WITH MONTELUKAST, TROGLITAZONE, FELODIPINE, AND 9-CIS-RETINOIC ACID
J. Biol. Chem., June 20, 2008; 283(25): 17227 - 17237.
[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 © 2007 by the American Society for Pharmacology and Experimental Therapeutics.