Methadone hydrochloride: effects of acute administration on disposition and hepatic function in guinea pigs

Abstract

d,l-Methadone hydrochloride (10 or 25 mg/kg body weight) was administered to adult female albino guinea pigs as either single doses or as daily doses for 6 consecutive days. A pharmacokinetic study was carried out on the animals receiving single doses, the plasma methadone being quantified by gas–liquid chromatography following solvent extraction. Different subgroups of animals receiving daily doses were killed after successive 24-h intervals for plasma and hepatic methadone residue analysis and for the in vitro measurement of hepatic monooxygenase (p-nitroanisole O-demethylase (OD); aniline hydroxylase (AH)) and glucuronyltransferase (GT) activities.No overt toxicity was observed at either dose administered. The β-phase plasma half-lives of the 10- and 25-mg/kg single doses were 13.2 and 13.8 h, respectively. Animals treated with six consecutive daily doses showed peak plasma and hepatic levels by day 2 of the treatment, followed by a gradual decline in subsequent days. The d,l-methadone did not significantly affect hepatic OD or AH though some reduction in activity was observed with the higher dose up to 7 days after stopping treatment. Significant reduction of GT activity was observed 24 h after the initial doses but, while the activities of animals receiving subsequent 10-mg/kg doses recovered, those of animals receiving 25-mg/kg doses remained significantly reduced even up to 7 days after treatment despite the fact that only traces of methadone could be detected in the livers.