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Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2006 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 32, no 3, 1134-1141 p.Article in journal (Refereed) Published
Abstract [en]

Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

Place, publisher, year, edition, pages
2006. Vol. 32, no 3, 1134-1141 p.
Keyword [en]
PET, ["C]verapamil, p-glycoprotein, cyclosporin, pharmacokinetics, modeling, blood-brain barrier, active efflux
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-96870DOI: 10.1016/j.neuroimage.2006.05.047ISI: 000240470300019PubMedID: 16857389OAI: oai:DiVA.org:uu-96870DiVA: diva2:171597
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2013-07-23Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 70
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
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
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-11-22Bibliographically approved

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Syvänen, StinaEriksson, OlofHammarlund-Udenaes, MargaretaLångström, Bengt
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Department of Pharmaceutical BiosciencesDepartment of Biochemistry and Organic Chemistry
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