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|Title:||Blood-brain distribution of morphine-6-glucuronide in sheep|
|Citation:||British Journal of Pharmacology, 2006; 149(6):754-760|
|Publisher:||Nature Publishing Group|
|H H Villesen, D J R Foster, R N Upton, L L Christrup, A A Somogyi, A Martinez and C Grant|
|Abstract:||Background and purpose: 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. Experimental approach: 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. Key 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. Conclusion and Implications: 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.|
|Keywords:||M6G (morphine-6-glucuronide); pharmacokinetics; drug distribution; blood–brain barrier; cerebral blood flow; sheep physiological model|
|Appears in Collections:||Anaesthesia and Intensive Care publications|
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