Ethanol inhibition of hepatic uptake of dl-[2-14C]methadone in the rat and its consequence.

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Abstract
The effect of concomitant administration of methadone and ethanol was studied in male Wistar rats intubated with 3 or 2.25 g of ethanol per kg of body wt (15% w/v [wt/vol]) and 5.6 or 5 mg per kg of dl-[2-14C]methadone. Blood and urine were collected between 15 min and 48 h; liver, kidney, muscle, perirenal fat, brain, plasma and the gastrointestinal tract and contents were collected at 0.5, 1, 4, 8 and 24 h. Radioactivity in bile consisted of methadone, 2-ethyl-5-methyl-3,3-diphenyl-2-ethylidine pyrrolidine (EMPD), dl-1,5-dimethyl-3,3-diphenyl-2-ethylidene pyrrolidine (EDDP) and the glucuronide of p-hydroxy-EMDP. The EDDP was the major metabolite in 0-24 h bile samples from control and ethanol-treated rats (34.5 and 43.6%, respectively). The concentration of radiolabel decreased in the tissues of controls and treated animals in the order liver > kidney > fat > muscle > plasma > brain over the time periods examined. A biphasic effect of ethanol was demonstrated in hepatic uptake of methadone and the biliary excretion of labeled EDDP, but was not observed in other tissues. In the ethanol-treated rats the liver/blood ratios of radioactivity were reduced at 0.5 and 1 h, but elevated (50 and 90%, respectively) by 4 and 8 h, and the bile samples showed an initial ethanol-induced inhibition of metabolism (0-4 h) followed by an apparent stimulation of hepatic metabolism (4-24 h). Blood and urine concentrations of radioactivity were elevated in the ethanol-treated animals at 0.25, 8, 12 and 18 h. The primary ethanol-induced biophysiological lesion appeared to be the inhibition of hepatic uptake of methadone, and all other pharmacokinetic changes were secondary. The inhibited hepatic uptake of methadone and the consequently elevated blood levels of the free drug could account for the misuse of alcohol by methadone-maintenance patients.