uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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.
Show others and affiliations
2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, p. 177-186Article 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, p. 177-186
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, id: diva2:1154462
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2018-03-27Bibliographically approved
In thesis
1. Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
Open this publication in new window or tab >>Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 254
Keyword
Blood-brain barrier, Neurovascular unit, Pharmacokinetics, Neurodegenerative disease, Drug transport, Brain tissue binding, Positron emission tomography, Brain regions
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-347204 (URN)978-91-513-0294-2 (ISBN)
Public defence
2018-05-18, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-04-26

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

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

Search in DiVA

By author/editor
Gustafsson, SofiaEriksson, JonasSyvänen, StinaEriksson, OlofHammarlund-Udenaes, MargaretaAntoni, Gunnar
By organisation
Department of Pharmaceutical BiosciencesOrganic Pharmaceutical ChemistryGeriatricsDivision of Molecular Imaging
In the same journal
NeuroImage
Radiology, Nuclear Medicine and Medical Imaging

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 133 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf