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

Authors

  • Rasmus S. Pedersen,

    1. Clinical Pharmacology, University of Southern Denmark and Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark
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  • Per Damkier,

    1. Clinical Pharmacology, University of Southern Denmark and Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark
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  • Kim Brosen

    1. Clinical Pharmacology, University of Southern Denmark and Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark
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Rasmus Steen Pedersen, Clinical Pharmacology, University of Southern Denmark, Winslowparken 19, DK-5000 Odense C, Denmark.
Tel: + 45 6550 3066
Fax: + 45 6591 6089
E-mail: rpedersen@health.sdu.dk

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 (= 0.0066) increase in the AUC0–∞ of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06–1.39]. The elimination half-life (t1/2) was also significantly higher (= 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 AUC0–∞ and t1/2 of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

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