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

Abstract

ObjectiveTo determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo). Study designCrossover experimental study. AnimalsA group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg [mean ± standard deviation (SD)]. MethodsMethadone 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 following 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. ResultsFollowing IV injection, systemic clearance (Clss) and volume of distribution (Vdss) 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 relevanceThe pharmacokinetic profile of IV methadone was characterized by a high Clss and large Vdss, with high bioavailability and absorption rate following 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.