Tissue distribution of levo-methadone in nonpregnant and pregnant female and male mice: effect of SKF 525-A 1,2.

Male, nonpregnant and pregnant female (15-17 gestational days) mice were injected i.p. with saline or SKF 525-A (50 mg/kg) and 1 hour later with levo-3H-1-methadone (205 mug/kg; 0.8 and 5 mg/kg). Levels of free methadone were examined in some or all of the following tissues: brain, plasma, liver, lung, spleen, kidney, heart, eye, placenta, amniotic fluid, whole fetus, fetal brain and liver. In saline controls, the methadone concentrations in several adult tissues, whole fetuses, fetal brain and liver reached peak levels at 15 minutes and were negligible at 24 hours. Tissue levels of methadone increased in a dose-related manner; however, the brain/plasma concentration ratios with the three doses were almost unity at 15 minutes, 1 hour and 3 hours. Among adult tissues with high concentrations were the lung, liver, kidney and spleen; the brain in contrast contained very low concentrations. No notable differences were detected in the tissue levels of methadone in males and nonpregnant females; however, in pregnant mice significantly higher levels were observed in the lung and the liver. Fetal brain, liver and whole fetus concentrations were approximately similar. At 15 minutes, the fetal brain contained about 3 times more methadone than the maternal brain and the difference increased at subsequent times. Nonpregnant females excreted somewhat larger amounts of 3H in the urine than did pregnant females. SKF 525-A markedly enhanced and prolonged the concentrations of methadone in all the adult and the fetal tissues and lowered urinary excretion of total radioactivity in nonpregnant and pregnant females. Marked increases in tissue radioactivity after SKF 525-A might be due to a combination of effects involving inhibition of drug metabolism, altered tissue distribution and lower urinary excretion.