The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs

Objective The objective was to examine the effects of inhibiting cytochrome P450 (CYP) on the pharmacokinetics of oral methadone in dogs. Study design Prospective non-randomized experimental trial. Animals Six healthy Greyhounds (three male and three female). Methods The study was divided into two phases. Oral methadone (mean = 2.1 mg kg-1 PO) was administered as whole tablets in Phase 1. In Phase 2 oral methadone (2.1 mg kg-1 PO) was administered concurrently with ketoconazole (13.0 mg kg-1 PO q 24 hours), chloramphenicol (48.7 mg kg-1 PO q 12 hours), fluoxetine (1.3 mg kg-1 PO q 24 hours), and trimethoprim (6.5 mg kg-1 PO q 24 hours). Blood was obtained for analysis of methadone plasma concentrations by liquid chromatography with mass spectrometry. The maximum plasma concentration (C(max)), time to C(max) (T(max)), and the area under the curve from time 0 to the last measurable time point above the limit of quantification of the analytical assay (AUC(0-LAST)) were compared statistically. Results The C(max) of methadone was significantly different (p = 0.016) for Phase 1 (5.5 ng mL-1) and Phase 2 (171.9 ng mL-1). The AUC(0-LAST) was also significantly different (p = 0.004) for Phase 1 (13.1 hour ng mL-1) and Phase 2 (3075.2 hour ng mL-1). Conclusion and clinical relevance Concurrent administration of CYP inhibitors with methadone significantly increased the area under the curve and plasma concentrations of methadone after oral administration to dogs. Further studies are needed assessing more clinically relevant combinations of methadone and CYP inhibitors.