Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain

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dc.contributor.authorUpton, R.
dc.date.issued2002
dc.descriptionPublisher's copy made available with the permission of the publisher © Australian Society of Anaesthetists
dc.description.abstractP-glycoprotein in the membranes of endothelial cells actively transports some drugs out of the brain. The theoretical effect of P-glycoprotein mediated drug efflux on the cerebral distribution volumes of drugs was examined, with particular emphasis on anaesthetic-related drugs (often characterized by moderate to high permeability across the blood brain barrier due to their lipophilicity and intermediate molecular weight). An analytical equation for the cerebral distribution volume in the presence of the efflux was derived, and validated by modelling the same system using differential equations. The efflux was shown to lower both the membrane and intracellular drug concentrations in parallel, and to reduce the time required for brain:blood equilibration. The net effect of the efflux was governed by the ratio of the P-glycoprotein drug clearance from the membrane (Pcl) and the permeability of the membrane (PS). It was therefore a balance between the rate that a drug could be pumped out of the membrane by the efflux system, and the rate that the drug leaked back in due to the permeability of the membrane for the drug. The effect of the efflux was therefore more pronounced for drugs with membrane-limited cerebral kinetics (e.g. morphine), but was nevertheless significant for drugs with more flow-limited kinetics (e.g fentanyl). The cerebral distribution volume was also influenced by the free fraction in blood and the free fraction in the intracellular space in the conventional manner. There are no theoretical limitations to the P-glycoprotein system influencing the cerebral distribution volume of moderately lipophilic anaesthetic-related drugs.
dc.description.urihttp://www.aaic.net.au/Article.asp?D=2001143
dc.identifier.citationAnaesthesia and Intensive Care, 2002; 30(2):183-191
dc.identifier.doi10.1177/0310057x0203000210
dc.identifier.issn0310-057X
dc.identifier.issn1448-0271
dc.identifier.orcidUpton, R. [0000-0001-9996-4886]
dc.identifier.urihttp://hdl.handle.net/2440/5896
dc.language.isoen
dc.publisherAustralian Soc Anaesthetists
dc.source.urihttps://doi.org/10.1177/0310057x0203000210
dc.subjectBlood-Brain Barrier
dc.subjectBrain
dc.subjectAnimals
dc.subjectHumans
dc.subjectAnesthetics
dc.subjectPharmacokinetics
dc.subjectModels, Theoretical
dc.subjectATP Binding Cassette Transporter, Subfamily B, Member 1
dc.titleTheoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain
dc.typeJournal article
pubs.publication-statusPublished

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