The effect of fluconazole on oral methadone in dogs

Objective To determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs. Study design Prospective, incomplete block. Animals A total of 12 healthy Beagle dogs. Methods Dogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg(-1)); oral fluconazole (5 mg kg(-1)) every 12 hours starting 24 hours prior to oral methadone (1 mg kg(-1)); oral fluconazole (2.5 mg kg(-1)) every 12 hours starting 24 hours prior to oral methadone (1 mg kg(-1)); and oral fluconazole (5 mg kg(-1)) every 24 hours starting 12 hours prior to oral methadone (1 mg kg(-1)). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (f(R)), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry. Results Significantly higher maximum plasma methadone concentration (mean, 25-46 ng mL(-1)) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL(-1)). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11-20 ng mL(-1). Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or fR among treatments. Conclusions and clinical relevance Fluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects.