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.
| Original language | English |
|---|---|
| Pages (from-to) | 397-402 |
| Number of pages | 6 |
| Journal | British Journal of Clinical Pharmacology |
| Volume | 58 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2004 Oct 1 |
| Externally published | Yes |
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Keywords
- CYP2C8
- Drug interaction
- Ketoconazole
- Pharmacokinetics
- Rosiglitazone
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
Cite this
Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. / Park, Ji-Young; Kim, Kyoung Ah; Shin, Jae Gook; Lee, Ki Young.
In: British Journal of Clinical Pharmacology, Vol. 58, No. 4, 01.10.2004, p. 397-402.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects
AU - Park, Ji-Young
AU - Kim, Kyoung Ah
AU - Shin, Jae Gook
AU - Lee, Ki Young
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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.
AB - 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.
KW - CYP2C8
KW - Drug interaction
KW - Ketoconazole
KW - Pharmacokinetics
KW - Rosiglitazone
UR - http://www.scopus.com/inward/record.url?scp=4744348757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4744348757&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2125.2004.02161.x
DO - 10.1111/j.1365-2125.2004.02161.x
M3 - Article
VL - 58
SP - 397
EP - 402
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
SN - 0306-5251
IS - 4
ER -