QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.018010v1 36/1/73    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tornio, A. Articles by Backman, J. T. Search for Related Content PubMed PubMed Citation Articles by Tornio, A. Articles by Backman, J. T.

Trimethoprim and the CYP2C8^*3 Allele Have Opposite Effects on the Pharmacokinetics of Pioglitazone

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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 of trimethoprim or placebo twice daily for 6 days. On day 3, they ingested 15 mg of pioglitazone. The effects of trimethoprim on pioglitazone were characterized in vitro. Trimethoprim raised the area under the plasma pioglitazone concentration-time curve (AUC_0–) 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 AUC_0– of pioglitazone was 34% smaller in the CYP2C8^*3/^*3 group and 26% smaller in the CYP2C8^*1/^*3 group than in the CYP2C8^*1/^*1 group (p < 0.05). Trimethoprim inhibited M-IV formation in vitro (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.

This article has been cited by other articles:

				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]

				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]