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Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Translationell PKPD)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.ORCID-id: 0000-0003-0241-092X
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. (Molekylär geriatrik/ Rudbecklaboratoriet)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
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2017 (engelsk)Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, 177-186 s.Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2017. Vol. 155, 177-186 s.
Emneord [en]
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
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Identifikatorer
URN: urn:nbn:se:uu:diva-332421DOI: 10.1016/j.neuroimage.2017.04.068ISI: 000405460900015PubMedID: 28467891OAI: oai:DiVA.org:uu-332421DiVA: diva2:1154462
Tilgjengelig fra: 2017-11-02 Laget: 2017-11-02 Sist oppdatert: 2017-11-02bibliografisk kontrollert

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