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Pharmacokinetic consequences of active drug efflux at the blood-brain barrier
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
2006 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 4, 705-717 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations. METHODS: Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin. RESULTS: The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K(p,uu). CONCLUSIONS: Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.

Place, publisher, year, edition, pages
2006. Vol. 23, no 4, 705-717 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96869DOI: 10.1007/s11095-006-9780-0PubMedID: 16575498OAI: oai:DiVA.org:uu-96869DiVA: diva2:171596
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-12-06Bibliographically approved
In thesis
1. Blood-Brain Barrier Transport: Investigation of Active Efflux using Positron Emission Tomography and Modelling Studies
Open this publication in new window or tab >>Blood-Brain Barrier Transport: Investigation of Active Efflux using Positron Emission Tomography and Modelling Studies
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis examines the transport of exogenous molecules across the blood-brain barrier (BBB), focusing on active efflux, using positron emission tomography (PET), computer simulation and modelling. P-glycoprotein (P-gp) inhibition was studied using [11C]verapamil and [11C]hydroxyurea was investigated as a new marker for active efflux transport. Simulations were carried out to explore the importance of the efflux transporter location in the BBB. Brain concentrations of [11C]verapamil, [11C]GR205171 and [18F]altanserin were compared in various laboratory animal species and in humans.

A central aspect of the studies has been the novel combination of dynamic PET imaging of the brain pharmacokinetics of a labelled drug, administered through an exponential infusion scheme allowing time-resolved consequence analysis of P-gp inhibition, and mathematical modelling of the obtained data. The methods are applicable to drugs under development and can be used not only in rodents but also in higher species, potentially even in humans, to investigate the effects of P-gp or other transporters on drug uptake in the brain.

The inhibition of P-gp by cyclosporin A (CsA) and the subsequent change in brain concentrations of [11C]verapamil occurred rapidly in the sense that [11C]verapamil uptake increased rapidly after CsA administration but also in the sense that the increased uptake was rapidly reversible. The P-gp inhibition was best described by an inhibitory indirect effect model in which CsA decreased the transport of [11C]verapamil out of the brain. The model indicated that approximately 90% of the transport of [11C]verapamil was P-gp-mediated. The low brain concentrations of [11C]hydroxyurea appeared to be a result of slow transport across the BBB rather than active efflux. This exemplifies why the extent and the rate of brain uptake should be approached as two separate phenomena. The brain-to-plasma concentration ratios for the three studied radiotracers differed about 10-fold be-tween species, with lower concentrations in rodents than in humans, monkeys and pigs. The increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species.

The findings demonstrate a need to include the dynamics of efflux inhibition in the experimental design and stress the importance of the choice of species in preclinical studies of new drug candidates.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 70
Keyword
Pharmaceutical biosciences, pharmacokinetics, P-glycoprotein, blood-brain barrier, modelling, PET, active efflux, species differences, [11C]verapamil, drug development, Farmaceutisk biovetenskap
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-8562 (URN)978-91-554-7126-2 (ISBN)
Public defence
2008-04-18, B42, Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-11-22Bibliographically approved

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Syvänen, StinaHammarlund-Udenaes, Margareta

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