BILIARY EXCRETION OF MORPHINE-3-GLUCURONIDE AND MORPHINE-3-ETHEREAL SULFATE BY DIFFERENT PATHWAYS IN THE RAT

¹ Department of Pharmacology, The Medical College of Wisconsin, and Clinical Pharmacology Service, Woods Veterans Administration Center, Milwaukee, Wisconsin

To advansce our understanding of biliary secretory mechanisms, the excretion in bile of morphine and its two metabolites, morphine-3-glucuronide (MG) and morphine-3-ethereal sunlfate (MES) were studied under several imposed conditions. ¹⁴C-morphine, MES or MG was administered i.v. and excretion was measured in anesthetized, renal-ligated rats in which the bile ducts were cannulated. Bile flow was increased by phenobarbital (PB) pretreatment and by raising body temperature from 31 to 39°C. Countercurrent distribution analyses showed that both MES and MG were excreted into bile largely in unchanged form. Morphine was extensively metabolized to MG before excretion. The major finding was that PB pretreatment enhanced the biliary excretions of MES whereas the biliary excretion of MG and morphine (as MG) was not increased. Furthermore, biliary excretion of MES was correlated with bile flow (r = 0.98), whereas biliary excretion of morphine (r = 0.44) and MG (r = 0.39) was not correlated with bile flow. Thus, the excretion of MES was enhanced by both PB pretreatment and raising body temperature, whereas the excretion of morphinse and MG was increased by raising body temperature only. The plasma disppearance of MES and MG was not affected by body temperature alteration or PB pretreatment. The disappearance from plasma of ¹⁴C after administration of ¹⁴C-morphine was not affected by changes in body temperature but was decreased by pretreatment with PB. Taken together this evidence indicates that MES and MG are excreted into bile along different pathways.