Abstract

The N-demethylation of methadone by 9000g supernatant fractions of hepatic homogenates was investigated in methadone-dependent rats. In these studies rats were administered methadone hydrochloride by allowing free access to the drug dissolved in the drinking water (0.5 mg/ml). Rats in the control group ingested tap water. The V_max of N-demethylation by liver supernatant fractions from methadone-dependent rats was 40-50% higher than that from control animals, whereas the K_m values did not differ significantly. The increase in V_max after chronic administration of methadone was not reflected by alteration of either the amount of cytochrome P-450 or the ethyl isocyanide binding. Diazepam was found to be a competitive inhibitor of N-demethylation of methadone with a K_i of 1.7 x 10^-4 M when incubated with hepatic supernatant fractions from control rats. However, diazepam was an uncompetitive inhibitor when incubated with supernatant fractions from livers of methadone-dependent rats. These data indicate that, unlike other opioid narcotics, methadone increased its own metabolism upon chronic treatment. Further, diazepam was shown to be a fairly effective inhibitor of the N-demethylation of methadone which may explain in part the enhanced effect of methadone observed in narcotic addicts when the combination is taken.