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Neuroimage. 2017 Jul 15;155:177-186. doi: 10.1016/j.neuroimage.2017.04.068. Epub 2017 Apr 30.

Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations.

Author information

1
Department of Pharmaceutical Biosciences; Translational PKPD, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: sofia.gustafsson@farmbio.uu.se.
2
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: jonas.eriksson@orgfarm.uu.se.
3
Department of Public Health and Caring Sciences; Molecular Geriatrics, Daghammarsköldsväg 20, 751 85 Uppsala, Sweden. Electronic address: stina.syvanen@pubcare.uu.se.
4
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: olof.eriksson@pet.medchem.uu.se.
5
Department of Pharmaceutical Biosciences; Translational PKPD, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: mhu@farmbio.uu.se.
6
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: gunnar.antoni@pet.medchem.uu.se.

Abstract

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 60min infusion of [N-methyl-11C]oxycodone in combination with a therapeutic dose of oxycodone and during a 60min 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.

KEYWORDS:

Blood-brain barrier; Microdialysis; Oxycodone; Pharmacokinetics; Positron emission tomography; Unbound concentration

[Indexed for MEDLINE]

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