Pharmacokinetics and innocuity of a single dose of intravenous, intramuscular, and subcutaneous methadone in the domestic rabbit (Oryctolagus cuniculus)

Background

This study describes the pharmacokinetics and adverse effects of methadone in six healthy female New Zealand white rabbits (Oryctolagus cuniculus).

Methods

In a randomized crossover study, methadone was administered at 0.3 mg/kg intravenously (IV), 0.6 mg/kg intramuscularly (IM), and 1 mg/kg subcutaneously (SC), with 10-day washout periods. The same catheter was used for IV methadone administration and blood sampling. Plasma methadone concentrations were determined by high-performance liquid chromatography-mass spectrometry immediately before and up to 24 hours after drug administration. Respiratory rates and sedation scores were assessed at each timepoint. Food and water intake, stool, and urine outputs were quantified.

Results

For IV, IM, and SC routes, the median elimination half-life was 2.3, 3.4, and 5.8, hours, respectively. Median clearance was 1.5 L/h/kg and the volume of distribution was 4.1 L/kg for the IV route. Median bioavailability for IM and SC was 21.5% and 18.0% respectively. Median maximum plasma concentrations were 41.8 and 26.4 ng/mL at 0.2 and 0.4 hours after IM and SC administration, respectively. High interindividual variability was noted. At the doses tested, methadone did not cause sedation. Water intake was decreased immediately after, and food intake was decreased two days after methadone administration. No effects were noted on urine, fecal production, and respiratory rate.

Conclusions and clinical relevance

At the doses administered, IV reached higher methadone plasmatic concentrations, followed by IM and SC. However, results obtained for the IV should be confirmed in future studies using different catheters for drug administration and blood collection. The minimum effective plasma concentration of methadone is unknown in rabbits; caution should therefore be used when extrapolating from other species. Further studies are warranted to evaluate the pharmacodynamics of methadone in rabbits.