STUDIES OF ENTEROHEPATIC CIRCULATION OF MORPHINE IN RAT

Abstract

The disposition of 14C-morphine was studied after gastrointestinal and s.c. administration to female rats. Morphine was rapidly and nearly completely absorbed from the small intestine. After s.c. administration approximately 1/2 the 5 mg/kg dose of morphine was excreted via the bile into the intestinal tract, largely as morphine glucuronide. Unlike morphine the glucuronide conjugate in bile was poorly absorbed from the small intestine where its hydrolysis occurred slowly. After administration into the cecum, hydrolysis of the conjugate was rapid, and the rate of absorption of radioactive material was similar to that of free morphine. Treatment of rats with lincomycin (500 mg/l in drinking H2O and 25 mg twice a day by gastric intubation for 4 days) significantly decreased cecal hydrolysis of the conjugate and the cecal absorption of radioactive material. Lincomycin treatment also increased fecal excretion of the conjugate in rats given morphine s.c. (5 mg/kg). Hydrolysis of morphine glucuronide is dependent upon the status of enteric bacteria and is a prerequisite to the enterohepatic circulation of morphine. After lincomycin treatment a greater percentage of radioactivity excreted in the urine was associated with free morphine. This could be explained by the demonstration of pH dependence of renal excretion of morphine and a 1st-pass effect for this drug.