Microsomal spectral properties and narcotic N-demethylase activity in methadone-dependent rats.
Rats were given access ad lib. to various concentrations (0.3 to 1.0 mg/ml) of methadone hydrochloride dissolved in sucrose solution. The N-demethylation of various narcotics was studied in hepatic preparations from methadone-consuming rats in order to determine if there was substrate specificity for the microsomal demethylase system. The Vmax for the N-demethylation of methadone, ethylmorphine, and meperidine was increased by 40-65%, whereas that for morphine N-demethylation was reduced to 55% of the control value. Additive or synergistic effects on microsomal cytochrome P-450 content were seen when methadone consumption was supplemented by administration of maximally inducing doses of either 3-methylcholanthrene (3-MC) or phenobarbital (PB). This suggested that there was an increase in a type of cytochrome P-450 which was independent of that induced by PB or 3-MC. The qualitative change in cytochrome P-450 reflected in the ethylisocyanide binding spectrum was also apparent after treatment with methadone, PB, or 3-MC, and the combination of methadone and PB exhibited effects that differed from PB alone. Two-substrate kinetic analysis with methadone and morphine as substrates indicated that more than one enzymic system may be involved in the N-demethylation reaction and that a common component of this N-demethylase system could not be induced with phenobarbital. However, methadone and meperidine seem to be demethylated by the same enzymic system.
D000818:Animals; D006801:Humans; D007700:Kinetics; D008297:Male; D008691:Methadone / Q000378:metabolism / Q000494:pharmacology*; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D019966:Substance-Related Disorders / Q000201:enzymology*
D008748:Methylcholanthrene; D009020:Morphine; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone; D010634:Phenobarbital