RT Journal Article SR Electronic T1 Trimethoprim and the CYP2C8*3 Allele Have Opposite Effects on the Pharmacokinetics of Pioglitazone JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 73 OP 80 DO 10.1124/dmd.107.018010 VO 36 IS 1 A1 Tornio, Aleksi A1 Niemi, Mikko A1 Neuvonen, Pertti J. A1 Backman, Janne T. YR 2008 UL http://dmd.aspetjournals.org/content/36/1/73.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics