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Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone
Tekijät: Tornio A, Niemi M, Neuvonen PJ, Backman JT
Kustantaja: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Julkaisuvuosi: 2008
Journal: Drug Metabolism and Disposition
Tietokannassa oleva lehden nimi: DRUG METABOLISM AND DISPOSITION
Lehden akronyymi: DRUG METAB DISPOS
Vuosikerta: 36
Numero: 1
Aloitussivu: 73
Lopetussivu: 80
Sivujen määrä: 8
ISSN: 0090-9556
DOI: https://doi.org/10.1124/dmd.107.018010
Tiivistelmä
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 ->infinity)) 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 ->infinity) 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 mu M), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.
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 ->infinity)) 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 ->infinity) 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 mu M), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.
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