Pharmacokinetics of methadone after intravenous and subcutaneous administration in domestic ferrets (Mustela putorius furo).

Abstract

Objective: To determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo).

Study design: Crossover experimental study.

Animals: A group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg (mean ± standard deviation).

Methods: Methadone hydrochloride (0.3 mg kg^-1) was injected IV or SC to each ferret with a 3 week washout period. Blood samples were collected via a jugular catheter before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360 and 480 minutes after drug administration. Liquid chromatography-tandem mass spectrometry was used to determine plasma methadone concentrations. A nonlinear mixed effects model was used to analyze the data.

Results: After IV injection, systemic clearance (Cl_ss) and volume of distribution (Vd_ss) were 78.9 mL min^-1 kg^-1 and 9.8 L kg^-1, respectively. Elimination half-life was 2.0 hours and SC bioavailability was fixed at 1. The maximum observed plasma concentration after SC injection was 92.1 ± 76.8 ng mL^-1. Behavioral changes were observed after both routes.

Conclusions and clinical relevance: The pharmacokinetic profile of IV methadone was characterized by a high Cl_ss and large Vd_ss, with high bioavailability and absorption rate after SC administration. Half-life was short and mean plasma methadone concentrations stayed above the minimum effective concentration (MEC) reported in humans only after SC administration for 5 minutes, but remained above that reported in dogs for 45 minutes following both routes. Further studies investigating the MEC and pharmacodynamics of methadone in ferrets are warranted.