Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone

Drug Metab Dispos. 2008 Jan;36(1):73-80. doi: 10.1124/dmd.107.018010. Epub 2007 Oct 3.

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 (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 muM), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Anti-Bacterial Agents / pharmacology*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Drug Interactions
  • Female
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Metabolic Clearance Rate
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Pioglitazone
  • Polymorphism, Single Nucleotide*
  • Thiazolidinediones / blood
  • Thiazolidinediones / pharmacokinetics*
  • Trimethoprim / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Trimethoprim
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Pioglitazone