Date of Award
11-1972
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
First Advisor
James M. Fujimoto
Second Advisor
G. B. Spurr
Abstract
The biliary excretion of morphine, roorphine-3-ethereal sulfate (MES) and morphine-3-glucuronide (MG) were studied under several imposed conditions. N-14c methyl labeled morphine, MES or MG was administered intravenously to anesthetized, renal ligated rats and biliary excretion determined over a 3 hour period. Bile flow was increased by daily pretreatment with phenobarbital (75 mg/kg, i.p.) for 4 days and by raising body temperature from 31 to 39°C. Countercurrent distribution analyses showed that administered MG and MES were excreted in bile primarily in unchanged form, whereas morphine was conjugated with glucuronic acid before being excreted. The major finding was that MES recovery in bile was correlated with bile flow (r = 0.98) while recovery of MG (r = 0.39) and morphine as MG (r = 0.44) was not correlated with bile flow. Furthermore, changes in body temperature and phenobarbital induction differentially affected the biliary excretion of MES and MG. It was, therefore, concluded that MES and MG were excreted into bile of the rat along different pathways.
To study the absorption of compounds from the biliary tree of the rat, a new technique, retrograde intrabiliary injection, was developed. It consisted of injecting compounds which were dissolved in isosmotic 0.9% saline retrogradely into the biliary tree over a 10 to 20 second period. The volume of solution administered by this route was 18, 25, 32, 39 or 46 μl. Upon completion of the retrograde injection a different compound, either sulfobromophthalein (0.25 mg) or 14C morphine (0.5 μc), was administered intravenously. Bile flow began immediately after the retrograde injection. The first 30 drops of bile were collected individually and analyzed for the compounds administered by the intrabiliary and intravenous routes. The results suggested that water is absorbed at the bile ducts and ductules, that retrogradely administered morphine undergoes absorption and metabolism followed by re-excretion of the metabolite (MG) at bile canaliculi, that urea is absorbed at sites intermediate to those of water absorption and morphine metabolite re-excretion and that inulin, erythritol and mannitol are poorly absorbed at all sites. These findings point out the need to consider reabsorption in studying biliary excretion mechanisms.