Co-administration of Fluoxetine Alters the Steady State Pharmacokinetics of Fluconazole after Multiple Oral Administration in Dogs

Abstract

Objectives. Fluconazole is an antifungal agent which has become the mainstay treatment of opportunistic fungal infections in immuno-compromized patients. Fluoxetine is a selective serotonine reuptake inhibitor used in the treatment of psychiatric disorders. In the current study we investigated the effect of chronic administration of fluoxetine on the steady state pharmacokinetics parameters of fluconazole. Methods. The pharmacokinetics of Fluconazole, following 10 mg/kg single and multiple oral dosing for 10 days, was determined in dogs. Subsequently, the effect of 2 mg/kg fluoxetine given for 10 days, on the pharmacokinetics of Fluconazole was investigated. Results. The co-administration resulted in significant reduction of 40.1% and 35.6% in AUC 0-∞ , and C max , respectively compared to fluconazole alone. A significant alteration of V ss/F was also seen as it increased from 0.242 ± 0.04 to 0.654 ± 0.17 l/kg (P < .01). Accordingly, a significant reduction in K el from 0.048 ± 0.01 hr-1 to 0.031 ± 0.01 was detected (P < .01). Conclusion. fluoxetine reduced plasma concentration of fluconazole. The mechanism of the interaction is probably the inhibition of OATP or other transporters in the intestinal wall. This interaction may have significant clinical importance because reduction in fluconazole may lead to treatment failure of fungal infection.

Pharmacokinetics of fluconazole after oral administration to healthy beagle dogs

“…There was a difference in the maximum plasma concentrations in this study compared with those in previous studies 12,17 . The reported C max in six beagles after a single administration of 10 mg/kg fluconazole was higher than that which we measured after a single administration with the same dose (12.05 versus 5.67 μg/mL).…”

“…There was a difference in the maximum plasma concentrations in this study compared with those in previous studies. 12,17 The reported C max in six beagles after a single administration of 10 mg/kg fluconazole was higher than that which we measured after a single administration with the same dose (12.05 versus 5.67 μg/ mL). The reasons for the differences are unclear, and they may be associated with differences in fluconazole formulations, sample processing, analytical methods and individual variation in drug absorption or metabolism.…”

“…However, only a few studies have been reported on the pharmacokinetics of fluconazole to determine the optimal dosing regimen in dogs. 12,17 Furthermore, the pharmacokinetics of 5 mg/kg fluconazole has not been studied. Therefore, this study aimed to determine the pharmacokinetics of fluconazole in healthy dogs after its oral administration in single and multiple doses, and to compare the pharmacokinetics at a dose of 5 mg/kg /day with that at a dose of 10 mg/kg/day.…”

“…However, only a few studies have been reported on the pharmacokinetics of fluconazole to determine the optimal dosing regimen in dogs 12,17 . Furthermore, the pharmacokinetics of 5 mg/kg fluconazole has not been studied.…”