title: Effect of multiple oral dosing of fluconazole on the pharmacokinetics of cyclosporine in healthy beagles.
abstract: Fluconazole (Fcz) is successfully used in human organ transplant patients as an antifungal therapy. However, Fcz can increase the cyclosporine (CsA) trough level and lead to CsA nephrotoxicity. In canine renal transplantation, CsA has been used as a major immunosuppressant, and it is important to control its trough level. However, the interaction of Fcz with CsA has not yet been reported in dogs. In this study, the effect of Fcz treatment on the pharmacokinetics of CsA in four healthy beagles was investigated using a four-period crossover design. The treatments included CsA alone (A), CsA + multiple-dose Fcz 50 mg (B), CsA + multiple-dose Fcz 25 mg (C) and CsA + single-dose Fcz 50 mg (D). Blood CsA concentrations were measured at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after CsA administration. The AUC(0-12) and C(max) values for treatment B were significantly higher than those for the other treatments. In particular, the AUC(0-12) of treatment B was about two times higher than that of treatment A. Fcz administration did not significantly prolong the half-life or mean residence time of CsA. The results of our study show that administration of multiple therapeutic doses of Fcz can significantly increase the CsA blood concentration, which might partially depend upon the Fcz blood concentration. When Fcz is used in CsA-based canine renal transplantation, it may be necessary to adjust the CsA trough level by decreasing the dose.
authors.affiliation: Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, Iwate, Japan. masaaki@iwate-u.ac.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Katayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Igarashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Tani
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nezu
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Harada
authors.forename: Takuya
authors.initials: T
authors.lastname: Yogo
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hara
authors.forename: Shinobu
authors.initials: S
authors.lastname: Aoki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000494:pharmacology*; D006207:Half-Life; D006262:Health; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D015725:Fluconazole