title: The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects.
abstract: OBJECTIVE
  To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.
  
  
  METHODS
  Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration.
  
  
  RESULTS
  The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone.
  
  
  CONCLUSIONS
  The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.
authors.affiliation: Clinical Pharmacology, University of Southern Denmark and Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark. rpedersen@health.sdu.dk
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.forename: Kim
authors.initials: K
authors.lastname: Brosen
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions / Q000235:genetics; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D010597:Pharmacogenetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000493:pharmacokinetics*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D016666:Fluvoxamine