title: Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone.
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.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D000328:Adult; D000483:Alleles; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*; D014295:Trimethoprim / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014295:Trimethoprim; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000077205:Pioglitazone