Blood-brain distribution of morphine-6-glucuronide in sheep.
OBJECTIVE
At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep.


METHODS
Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements.


RESULTS
A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2.


CONCLUSIONS
Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.
Villesen
H H
HH
Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. hv@dfuni.dk
Foster
D J R
DJ
Upton
R N
RN
Christrup
L L
LL
Somogyi
A A
AA
Martinez
A
A
Grant
C
C
D000818:Animals; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D009022:Morphine Derivatives / Q000097:blood / Q000493:pharmacokinetics*; D012756:Sheep
D009022:Morphine Derivatives; C035349:morphine-6-glucuronide