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
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This study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation, Finland.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018010.
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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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