Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects.

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Park JY, Kim KA, Shin JG, Lee KY

Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects.

Br J Clin Pharmacol. 2004 Oct;58(4):397-402. doi: 10.1111/j.1365-2125.2004.02161.x.

PubMed ID

15373932 [ View in PubMed

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Abstract

AIMS: Fungal infection is a significant comorbidity in patients with diabetes mellitus, and ketoconazole, an antifungal agent, causes a number of drug interactions with coadministered drugs. Rosiglitazone is a novel thiazolidinedione antidiabetic drug, mainly metabolized by CYP2C8 and to a lesser extent CYP2C9. We investigated the possible effect of ketoconazole on the pharmacokinetics of rosiglitazone in humans. METHODS: Ten healthy Korean male volunteers were treated twice daily for 5 days with 200 mg ketoconazole or with placebo, using a randomized, open-label, two-way crossover study. On day 5, a single dose of 8 mg rosiglitazone was administered orally, and plasma rosiglitazone concentrations were measured. RESULTS: Ketoconazole increased the mean area under the plasma concentration-time curve for rosiglitazone by 47%[P = 0.0003; 95% confidence interval (CI) 23, 70] and the mean elimination half-life from 3.55 to 5.50 h (P = 0.0003; 95% CI in difference 1.1, 2.4). The peak plasma concentration of rosiglitazone was increased by ketoconazole treatment by 17% (P = 0.03; 95% CI 5, 29). The apparent oral clearance of rosiglitazone decreased by 28% after ketoconazole treatment (P = 0.0005; 95% CI 18, 38). CONCLUSIONS: This study revealed that ketoconazole affected the disposition of rosiglitazone in humans, probably by the inhibition of CYP2C8 and CYP2C9, leading to increasing rosiglitazone concentrations that could increase the efficacy of rosiglitazone or its adverse events.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ketoconazole	Cytochrome P450 2C8	Protein	Humans	Unknown	Inhibitor	Details
Ketoconazole	Cytochrome P450 2C9	Protein	Humans	Unknown	Inhibitor	Details