The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects

Br J Clin Pharmacol. 2006 Dec;62(6):682-9. doi: 10.1111/j.1365-2125.2006.02706.x. Epub 2006 Jul 12.


Aims: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cytochrome P-450 CYP2C8
  • Drug Interactions / genetics
  • Female
  • Fluvoxamine / pharmacology*
  • Genotype
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Pharmacogenetics
  • Rosiglitazone
  • Thiazolidinediones / pharmacokinetics*


  • Antidepressive Agents, Second-Generation
  • Blood Glucose
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Rosiglitazone
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Fluvoxamine