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Intestinal absorption and stability of morphine 6-glucuronide in different physiological compartments of the rat
F Stain-Texier1, P Sandouk, J M Scherrmann
1INSERM, Unité 26 and Département de Pharmacocinétique de la Faculté de Pharmacie, Paris, France.
Abstract:
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.
Insights
Morphine 6-glucuronide (M6G) is minimally hydrolyzed to morphine in the gastrointestinal tract and liver. Oral M6G absorption is primarily as the parent compound, exhibiting slow-release characteristics.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Morphine 6-glucuronide (M6G) is an active metabolite of morphine with potential therapeutic applications.
- The extent of M6G hydrolysis to morphine in vivo remains a subject of debate.
Purpose of the Study:
- To investigate the stability and metabolic fate of M6G following oral administration in rats.
- To determine the extent of M6G hydrolysis to morphine in various physiological compartments and ex vivo systems.
Main Methods:
- Acidic hydrolysis of M6G was assessed.
- Stability of M6G was studied in rat intestinal and colon contents.
- Ex vivo studies utilized an isolated perfused rat liver model.
- In vivo oral administration of M6G in rats followed by pharmacokinetic analysis.
Main Results:
- Acidic hydrolysis of M6G yielded less than 5% morphine.
- In the colon, M6G hydrolysis resulted in 85.6% morphine formation; hydrolysis was <2% in the small intestine.
- The isolated perfused rat liver showed low M6G hepatic extraction (0.04) and high biliary excretion (88.7%).
- In vivo, M6G was absorbed intact, with enterohepatic recirculation prolonging its absorption.
- Plasma concentrations showed minimal morphine (10.5%) and some morphine 3-glucuronide (M3G) (12.9%) relative to M6G.
Conclusions:
- M6G exhibits significant stability in the upper gastrointestinal tract and liver.
- High M6G hydrolysis occurs in the colon, suggesting a role for gut microbiota.
- Oral M6G behaves as a slow-release formulation due to intact absorption and enterohepatic recirculation, with limited conversion to morphine.