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) i nduces 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: e xtracellular 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 micr odialysis was used to assess their distributions in the brain ECF. Conventi onal tissue homogenization was used to determine the distribution in the co rtex and whole brain. These two procedures were combined to estimate drug d istribution 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 C-max and AUC 4-5 times more higher, T-max shorter, and V(Z)f(-1) (v olume of distribution) and CL f(-1) (clearance) 4-6 times lower. The concen trations of the compounds in various brain compartments also differed: AUC values for M6G were lower than those of morphine in tissue and CSF and high er in brain ECF. AUC values in brain show that morphine levels were four ti mes higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF th an in ICS. 4 Morphine entered brain cells, whereas M6G was almost exclusively extracel lular. This high extracellular concentration, coupled with extremely slow d iffusion into the CSF, indicates that M6G was predominantly trapped in the extracellular fluid and therefore durably available to bind at opioid recep tors.