Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability.

1 This study was done to find out how morphine 6-beta-D-glucuronide (M6G) induces more potent central analgesia than morphine, despite its poor blood-brain barrier (BBB) permeability. The brain uptake and disposition of these compounds were investigated in plasma and in various brain compartments: extracellular fluid (ECF), intracellular space (ICS) and cerebrospinal fluid (CSF). 2 Morphine or M6G was given to rats at 10 mg kg(-1) s.c. Transcortical microdialysis was used to assess their distributions in the brain ECF. Conventional tissue homogenization was used to determine the distribution in the cortex and whole brain. These two procedures were combined to estimate drug distribution in the brain ICS. The blood and CSF pharmacokinetics were also determined. 3 Plasma concentration data for M6G were much higher than those of morphine, with Cmax and AUC 4-5 times more higher, Tmax shorter, and VZf-1 (volume of distribution) and CL f(-1) (clearance) 4-6 times lower. The concentrations of the compounds in various brain compartments also differed: AUC values for M6G were lower than those of morphine in tissue and CSF and higher in brain ECF. AUC values in brain show that morphine levels were four times higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF than in ICS. 4 Morphine entered brain cells, whereas M6G was almost exclusively extracellular. This high extracellular concentration, coupled with extremely slow diffusion into the CSF, indicates that M6G was predominantly trapped in the extracellular fluid and therefore durably available to bind at opioid receptors.

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.