Uptake, 3-, and 6-glucuronidation of morphine in isolated cells from stomach, intestine, colon, and liver of the guinea pig.

Orally administered morphine undergoes a considerable first-pass glucuronidation in animals and humans. However, the respective contribution of the gastrointestinal tract and the liver to the formation of the analgetically highly potent morphine-6-glucuronide (M6G) and the inactive morphine-3-glucuronide (M3G) is still debated. In this study, morphine uptake and biotransformation to M3G and M6G were compared in isolated cells from stomach, intestine, colon, and liver of the guinea pig. Morphine was taken up by all cell types in a time-dependent manner. There was evidence for a carrier-mediated accumulation in liver cells, but not in the other cell types. Morphine was glucuronidated to M3G by gastric, intestinal, colonic, and liver cells, and to M6G by all cell types excepted gastric cells. The M3G/M6G ratio averaged 3.5, 4.7, and 5.4 for colonic, intestinal, and liver cells, respectively. At low (1 microM) morphine concentration, glucuronidation rates for M3G and M6G in intestinal cells (88 and 20 pmol x mg protein-1 x hr-1, respectively) were similar to those in liver cells (133 and 12 pmol x mg protein-1 x hr-1, respectively). At high concentration (100 microM), rates of M3G and M6G formation in liver cells exceeded by 5- to 10-fold those of intestinal or colonic cells. In conclusion, the epithelium of the small and large intestine contributes with the liver to the formation of the active M6G; at the same time, the gastric, intestinal, and colonic epithelia are involved in the inactivation of morphine to M3G.