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Research ArticleArticle

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

Aleksi Tornio, Mikko Niemi, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 2008, 36 (1) 73-80; DOI: https://doi.org/10.1124/dmd.107.018010
Aleksi Tornio
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Mikko Niemi
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Pertti J. Neuvonen
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Janne T. Backman
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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 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 (AUC0–∞) 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–∞ 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.

Footnotes

  • This study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation, Finland.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.018010.

  • ABBREVIATIONS: P450, cytochrome P450; AUC, area under concentration-time curve; ANOVA, analysis of variance; HLM, human liver microsomes.

    • Received August 1, 2007.
    • Accepted October 2, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (1)
Drug Metabolism and Disposition
Vol. 36, Issue 1
1 Jan 2008
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Research ArticleArticle

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

Aleksi Tornio, Mikko Niemi, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 1, 2008, 36 (1) 73-80; DOI: https://doi.org/10.1124/dmd.107.018010

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Research ArticleArticle

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

Aleksi Tornio, Mikko Niemi, Pertti J. Neuvonen and Janne T. Backman
Drug Metabolism and Disposition January 1, 2008, 36 (1) 73-80; DOI: https://doi.org/10.1124/dmd.107.018010
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