The effects of desipramine (DMI) given i.p. 1 hour before administration of 14C-methadone (5 mg/kg s.c.) on the excretion of methadone in bile, feces and urine were studied. Rats with cannulated bile ducts excreted 52% of administered 14C into bile within 4 hours, 60% of the excretion as 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 30% as water-soluble metabolite (WSM). The percentages of 14C excreted within 48 hours into the feces and urine of rats without biliary fistula were 60.6 and 17.4%, respectively. The excretion of 14C in feces consisted mostly of EDDP. Urinary excretion consisted of unchanged methadone, EDDP and WSM in the first 12 hours and consisted mostly of WSM thereafter. DMI treatment increased biliary flow but decreased the biliary excretion of 14C, mainly by a decrease in WSM. The fecal output was greatly decreased by DMI, thus decreasing fecal excretion of 14C in the first 12 hours. DMI treatment markedly decreased urinary volume but did not change the urine pH. The decreased urinary excretion of WSM in DMI-treated rats during the first 12-hour urine sample accounted for most of the decreased elimination of 14C. It is suggested that DMI-induced inhibition of methadone metabolism in the liver is a major factor responsible for the observed decreases in the biliary and urinary excretion of WSM...