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Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0001-5466-8370
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-9181-1321
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2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, p. 482-491Article in journal (Refereed) Published
Abstract [en]

Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain), in aged A beta PP-transgenic mice, alpha-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5,1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value. Despite A beta or alpha-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology. (C) 2017 The Authors. Published by Elsevier Ltd.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 128, p. 482-491
Keywords [en]
Blood-brain barrier, Pharmacokinetics, Drug transport, Disease, Amyloid beta, Alpha-synuclein
National Category
Neurology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-340458DOI: 10.1016/j.neuropharm.2017.08.002ISI: 000418977200043PubMedID: 28797721OAI: oai:DiVA.org:uu-340458DiVA, id: diva2:1183094
Available from: 2018-02-15 Created: 2018-02-15 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
Keywords
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)
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Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-10-08

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