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https://hdl.handle.net/2440/22734
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Type: | Journal article |
Title: | Blood-brain distribution of morphine-6-glucuronide in sheep |
Author: | Villesen, H. Foster, D. Upton, R. Christrup, L. Somogyi, A. Martinez, A. Grant, C. |
Citation: | British Journal of Pharmacology, 2006; 149(6):754-760 |
Publisher: | Nature Publishing Group |
Issue Date: | 2006 |
ISSN: | 0007-1188 1476-5381 |
Statement of Responsibility: | 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 |
DOI: | 10.1038/sj.bjp.0706916 |
Published version: | http://dx.doi.org/10.1038/sj.bjp.0706916 |
Appears in Collections: | Anaesthesia and Intensive Care publications Aurora harvest 6 |
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