Tolerance to methadone lethality and microsomal enzyme induction in mice tolerant to and dependent on morphine.
In an attempt to explain a loss of cross-tolerance between morphine and methadone and an increased tolerance to methadone lethality in morphine-dependent mice administered methadone orally for six days, the possibility that methadone was stimulating its own metabolism was investigated. It was found that methadone did enhance its own metabolism two-fold. This increase in activity correlated with the development of tolerance to the lethal effects of methadone as measured by an elevation of the oral methadone LD50. Furthermore, SKF-525A, a potent microsomal inhibitor, abolished this tolerance. The intracerbroventricular methadone LD50 was not altered by six days administration of oral methadone, suggesting that the tolerance observed was dispositional in nature.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004361:Drug Tolerance; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic; D007928:Lethal Dose 50; D008099:Liver / Q000201:enzymology; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology
D009020:Morphine; D011335:Proadifen; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone