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Published on: July 29, 2014
Blood-brain distribution of morphine-6-glucuronide in sheep
H H Villesen1, D J R Foster, R N Upton
1Department of Pharmacology and Pharmacotherapy, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. hv@dfuni.dk
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.
Insights
Morphine-6-glucuronide (M6G) brain-blood partitioning is slow, primarily limited by blood-brain barrier permeability. This pharmacokinetic study in sheep reveals M6G
Area of Science:
- Pharmacology
- Neuroscience
- Drug Metabolism
Background:
- Limited data exists on the brain-blood partitioning of morphine-6-glucuronide (M6G), an active metabolite of morphine.
- Understanding M6G's cerebral kinetics is crucial for its clinical use and potential central nervous system effects.
Purpose of the Study:
- To determine the rate and extent of M6G partitioning into the brain.
- To investigate the cerebral kinetics of M6G following intravenous infusion in conscious sheep.
Main Methods:
- Intravenous infusion of M6G (2.2 mg kg(-1) over 4 minutes) in five instrumented sheep.
- Non-linear mixed-effects analysis with hybrid physiologically based kinetic models.
- Estimation of cerebral kinetics using arterio-sagittal sinus concentration gradients and cerebral blood flow.
Main Results:
- A membrane-limited model best described M6G blood-brain equilibration.
- Slow equilibration observed: 5.8 minutes to reach 50% equilibration in the deep compartment.
- Low membrane permeability (PS: 2.5 ml min(-1)) and a small deep distribution volume (V2: 18.4 ml) were found.
Conclusions:
- Cerebral pharmacokinetic modeling of M6G indicates delayed brain-blood equilibration.
- Blood-brain barrier permeability is the primary limitation for M6G brain entry, consistent with its physicochemical properties.
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