title: Blood-brain distribution of morphine-6-glucuronide in sheep.
abstract: 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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. hv@dfuni.dk
authors.forename: H H
authors.initials: HH
authors.lastname: Villesen
authors.forename: D J R
authors.initials: DJ
authors.lastname: Foster
authors.forename: R N
authors.initials: RN
authors.lastname: Upton
authors.forename: L L
authors.initials: LL
authors.lastname: Christrup
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: C
authors.initials: C
authors.lastname: Grant
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D009022:Morphine Derivatives / Q000097:blood / Q000493:pharmacokinetics*; D012756:Sheep
chemical_list: D009022:Morphine Derivatives; C035349:morphine-6-glucuronide