Studies of the enterohepatic circulation of morphine in the rat

The disposition of 14C-morphine was studied after gastrointestinal and subcutaneous administration to female Sprague-Dawley rats. Morphine was found to be rapidly and nearly completely absorbed from the small intestine. After s.c. administration, approximately half 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, however, 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/1 in drinking water 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). These findings indicated that hydrolysis of morphine glucuronide is dependent upon the status of enteric bacteria and is a prerequisite to the enterohepatic circulation of morphine. In addition, after lincomycin treatment, a greater percentage of radioactivity excreted in the urine was associated with free morphine. This finding could be expained by the demonstration of pH dependence of renal excretion of morphine and a first-pass effect for this drug.