Premium
The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects
Author(s) -
Pedersen Rasmus S.,
Damkier Per,
Brosen Kim
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02706.x
Subject(s) - rosiglitazone , pharmacokinetics , fluvoxamine , cyp2c8 , pharmacology , oral administration , medicine , endocrinology , metabolism , receptor , fluoxetine , cytochrome p450 , cyp3a4 , serotonin
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–∞ 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–∞ and t 1/2 of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.