The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects.
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.
Pedersen
Rasmus S
RS
Clinical Pharmacology, University of Southern Denmark and Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark. rpedersen@health.sdu.dk
Damkier
Per
P
Brosen
Kim
K
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*
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