| Abstract: | Treatment of rats with desipramine (DMI) 1 hour before the subcutaneous administration of methadone increased the intensity and prolonged the duration of methadone analgesia, as determined by the hot plate method. DMI significantly reduced the analgesic ED50 of methadone from a control value of 3.4 to 1.6 or 0.5 mg/kg in rats treated with 20 or 30 mg/kg of DMI, respectively. DMI treatment also significantly reduced the LD50 of methadone. DMI (20 mg/kg i.p.) was given 1 hour prior to administration of 14C-methadone (5 mg/kg s.c.) and the distribution of total 14C, unchanged methadone and methadone metabolites in various tissues was studied. DMI treatment greatly increased the brain uptake of 14C and the methadone brain/plasma concentration ratios for up to 3 hours. The concentrations of 14C and unchanged methadone were higher in kidneys and lower in lungs of DMI-treated rats as compared to controls. However, the ratios of unchanged methadone to its metabolites in kidneys and lungs were not changed significantly by DMI treatment. The level of unchanged methadone in liver was markedly elevated by DMI treatment at 45 and 90 minutes (190 and 183% of controls, respectively). The level of a water-soluble glucuronide metabolite of methadone was significantly decreased at 45-, 90- and 180-minute intervals (37, 36 and 54% of controls, respectively.) However, the total 14C in liver and the concentrations of two N-demethylated metabolites of methadone were not changed significantly. In vitro addition of DMI to liver microsomal incubations resulted in inhibition of the N-demethylation of methadone. It is suggested that DMI potentiated and prolonged methadone analgesia by increasing the brain concentration of methadone and by inhibiting metabolism of methadone in the liver. |
