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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 (Engelska)Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, s. 177-186Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2017. Vol. 155, s. 177-186
Nyckelord [en]
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:uu:diva-332421DOI: 10.1016/j.neuroimage.2017.04.068ISI: 000405460900015PubMedID: 28467891OAI: oai:DiVA.org:uu-332421DiVA, id: diva2:1154462
Tillgänglig från: 2017-11-02 Skapad: 2017-11-02 Senast uppdaterad: 2018-03-27Bibliografiskt granskad
Ingår i avhandling
1. Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
Öppna denna publikation i ny flik eller fönster >>Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

A high unmet medical need in the area of CNS diseases coincides with high failure rates in CNS drug development. Efficient treatment of CNS disease is constrained by limited entrance of drugs into the brain owing to the blood-brain barrier (BBB), which separates brain from blood. Insufficient inter-species translation and lack of methods to evaluate therapeutic, unbound, drug concentrations in human brain also contribute to development failure. Further disease related changes in BBB properties and tissue composition raise a concern of altered drug neuropharmacokinetics (neuroPK) during disease. This calls for the evaluation of translational aspects of neuroPK parameters in health and disease, and exploration of strategies for neuroPK translations between rodents and humans.

Positron emission tomography (PET) enables corresponding PK analysis in various species, although being restricted to measuring total, i.e. both unbound and nonspecifically bound, drug concentrations. However, the current work shows that PET can be used for the estimation of unbound, active, brain concentrations and for assessment of drug BBB transport, if compensation is made for intra-brain drug distribution and binding. Adapted PET designs could be applied in humans where rat estimates of drug intra-brain distribution may be used with reasonable accuracy for concentration conversions in healthy humans, but preferably not in Alzheimer’s disease (AD) patients. As shown in this thesis, a high variability in nonspecific drug tissue binding was observed in AD compared to rats and human controls that might lead to unacceptable bias of outcome values if used in PET. Furthermore, heterogeneity in drug tissue binding among brain regions in both rodents and humans was detected and must be considered in regional investigations of neuroPK. By the use of transgenic animal models of amyloid beta and alpha-synuclein pathology, the work further suggests that the BBB is able to uphold sufficient capacity for the transport of small molecular drugs and integrity towards large molecules despite the presence of hallmarks representative of neurodegenerative diseases.

This thesis work provides insight into neurodegenerative disease impact on neuroPK and contributes with translational strategies for neuroPK evaluation from preclinical investigations to the clinic, aimed to aid drug development and optimal disease management.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 75
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 254
Nyckelord
Blood-brain barrier, Neurovascular unit, Pharmacokinetics, Neurodegenerative disease, Drug transport, Brain tissue binding, Positron emission tomography, Brain regions
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-347204 (URN)978-91-513-0294-2 (ISBN)
Disputation
2018-05-18, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-04-26 Skapad: 2018-03-27 Senast uppdaterad: 2018-04-26

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

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Institutionen för farmaceutisk biovetenskapAvdelningen för organisk farmaceutisk kemiGeriatrikAvdelningen för Molekylär Avbildning
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