The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects.
Br J Clin Pharmacol
; 62(6): 682-9, 2006 Dec.
Article
en En
| MEDLINE
| ID: mdl-16856883
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hidrocarburo de Aril Hidroxilasas
/
Fluvoxamina
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Antidepresivos de Segunda Generación
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Tiazolidinedionas
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Hipoglucemiantes
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2006
Tipo del documento:
Article
País de afiliación:
Dinamarca