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 controversial. 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 under 2% in the small intestine, whereas the formation of morphine in colon feces represented 85.6 +/- 12.9% of the initial concentration of M6G. 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 was prolonged over the 24-hr experiment due to its reabsorption following enterohepatic recirculation. Finally, 10.5 +/- 4.3% of morphine and 12.9 +/- 5.1% of M3G compared with M6G AUCs were found in plasma. These results show that M6G is weakly converted into morphine when orally absorbed, with a kinetic profile similar to a slow release formulation.
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INSERM, Unité 26 and Département de Pharmacocinétique de la Faculté de Pharmacie, Paris, France.
Sandouk
P
P
Scherrmann
J M
JM
D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006868:Hydrolysis; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine