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Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translationell PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0003-0241-092X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molekylär geriatrik/ Rudbecklaboratoriet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, 177-186 p.Article in journal (Refereed) Published
Abstract [en]

Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography ( PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

Place, publisher, year, edition, pages
2017. Vol. 155, 177-186 p.
Keyword [en]
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-332421DOI: 10.1016/j.neuroimage.2017.04.068ISI: 000405460900015PubMedID: 28467891OAI: oai:DiVA.org:uu-332421DiVA: diva2:1154462
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2017-11-02Bibliographically approved

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Gustafsson, SofiaEriksson, JonasSyvänen, StinaEriksson, OlofHammarlund-Udenaes, MargaretaAntoni, Gunnar

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Gustafsson, SofiaEriksson, JonasSyvänen, StinaEriksson, OlofHammarlund-Udenaes, MargaretaAntoni, Gunnar
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Department of Pharmaceutical BiosciencesOrganic Pharmaceutical ChemistryGeriatricsDivision of Molecular Imaging
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