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Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2008 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 12, 5386-5400 p.Article in journal (Refereed) Published
Abstract [en]

This article describes the experimental set-up and pharmacokinetic modeling of P-glycoprotein function in the rat blood-brain barrier using [(11)C]verapamil as the substrate and cyclosporin A as an inhibitor of P-gp. [(11)C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady-state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [(11)C]verapamil infusion. The brain uptake of [(11)C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [(11)C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA-induced P-gp inhibition. The brain pharmacokinetics of [(11)C]verapamil was well described by a two-compartment model. The effect of CsA on the uptake of [(11)C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [(11)C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 microg/mL (4.1 microM). The model parameters indicated that 93% of the outward transport of [(11)C]verapamil was P-gp mediated.

Place, publisher, year, edition, pages
2008. Vol. 97, no 12, 5386-5400 p.
Keyword [en]
PET, pharmacokinetics, pharmacokinetic/pharmacodynamic models, P-glycoprotein, blood-brain barrier, active transport, drug interactions, efflux pumps, metabolism, population pharmacokinetics/pharmacodynamics
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96871DOI: 10.1002/jps.21359ISI: 000261313200030PubMedID: 18384156OAI: oai:DiVA.org:uu-96871DiVA: diva2:171598
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2017-12-14Bibliographically 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
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Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-11-22Bibliographically approved

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Syvänen, StinaHooker, AndrewBlomquist, GunnarLångström, BengtHammarlund-Udenaes, Margareta

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