Effect of phenobarbital pretreatment on the metabolism and biliary excretion of methadone

Abstract

The effect of phenobarbital (PB) pretreatment on the biliary excretion of methadone in rats was studied. Possible mechanisms by which PB pretreatment altered the biliary excretion of methadone were considered and studies in vitro on the metabolism of methadone were correlated with findings in vivo. For the biliary excretion studies, 14C-methadone was administered intravenously and biliary excretion measured in anesthetized renal-ligated rats in which the common bile duct was cannulated. PB pretreatment increased the biliary excretion of 14C after 14C-methadone administration. The different metabolites of methadone formed in vivo and excreted into bile were separated by thin-layer chromatography and quantitated. The biliary excretion of the metabolite which results from N-demethylation and cyclization of methadone was not altered by PB pretreatment. However, the biliary excretion of metabolites which result from further N-demethylation, hydroxylation and glucuronidation was increased by PB pretreatment. Several determinants of biliary excretion (i.e. bile flow, hepatic blood flow and metabolism). which are enhanced by PB pretreatment, could cause the observed increase in the biliary excretion of methadone. Of these possibilities, we feel the data best support the suggestion that enhancement of methadone metabolism by PB pretreatment is responsible for the increased biliary excretion of methadone in PB-pretreated rats. Furthermore, metabolism studies in vitro, using microsomes from PB-treated rats, support the suggestion that PB pretreatment enhances the metabolism of methadone in vivo.