Blood–brain distribution of morphine‐6‐glucuronide in sheep

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.

DOI: 10.1038/sj.bjp.0706916

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