Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs

Abstract

ObjectiveTo assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. Study designNon-randomized, sequential design. AnimalsSix healthy Greyhound dogs (three male, three female). MethodsCanine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. ResultsSignificant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL−1) and CMAX (6 ng mL−1) of methadone significantly increased to 541 hours ng mL−1 and 47.8 ng mL−1, respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. Conclusions and clinical relevanceThis study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment.