title: Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Gachon Medical School and Clinical Trial Centre, Gil Medical Centre, Incheon, Korea. jypark@gachon.ac.kr
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Kyoung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Lee
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007654:Ketoconazole