INTESTINAL-ABSORPTION AND STABILITY OF MORPHINE 6-GLUCURONIDE IN DIFFERENT PHYSIOLOGICAL COMPARTMENTS OF THE RAT

Morphine 6-glucuronide (M6G) is an active metabolite of morphine that could be used as a drug, but its hydrolysis into morphine remains cont roversial. We investigated the acidic hydrolysis of M6G and found that the recovery of morphine did not exceed 5%. The stability of M6G was studied in different physiological compartments of male Sprague-Dawley rats. The formation of morphine after M6G incubation in feces was und er 2% in the small intestine, whereas the formation of morphine in col on feces represented 85.6 +/- 12.9% of the initial concentration of M6 G. The stability of M6G was also determined ex vivo using the isolated perfused rat liver. The hepatic extraction ratio of M6G was very low (0.04 +/- 0.02), but 88.7 +/- 11.2% of the dose was excreted in bile. The elimination half-life of M6G in the perfusate (66.4 +/- 20.6 min) was higher than the elimination half-life in bile (18.6 +/- 2.5 min). The hydrolysis of M6G was low, with only 7.7% and 0.03% of morphine in the perfusate and bile, respectively. The perfusate level of morphine 3-glucuronide (M3G) resulting from morphine conjugation was 4.9 +/- 3 .6%, An in vivo experiment demonstrated that after oral administration , M6G was absorbed per se in the proximal intestine, and the process w as prolonged over the 24-hr experiment due to its reabsorption followi ng enterohepatic recirculation. Finally, 10.5 +/- 4.3% of morphine and 12.9 +/- 5.1% of M3G compared with M6G AUCs were found in plasma. The se results show that M6G is weakly converted into morphine when orally absorbed, with a kinetic profile similar to a slow release formulatio n.