Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects
Article first published online: 27 JUL 2004
British Journal of Clinical Pharmacology
Volume 58, Issue 4, pages 397–402, October 2004
How to Cite
Park, J.-Y., Kim, K.-A., Shin, J.-G. and Lee, K. Y. (2004), Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. British Journal of Clinical Pharmacology, 58: 397–402. doi: 10.1111/j.1365-2125.2004.02161.x
- Issue published online: 27 JUL 2004
- Article first published online: 27 JUL 2004
- Received 21 January 2004 Accepted 30 March 2004
- drug interaction;
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.
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.
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).
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.