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Rate of Small-Molecular Drug Transport Across the Blood-Brain Barrier in a Pericyte-Deficient State
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. (Vascular Biology)ORCID iD: 0000-0002-8494-971x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD)ORCID iD: 0000-0002-9181-1321
2018 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 124, p. 182-187Article in journal (Refereed) Published
Abstract [en]

Close interactions between pericytes and brain endothelial cells are essential for keeping the blood-brain barrier (BBB) functional and to restrict the transport of various xenobiotics from blood circulation to the brain parenchyma. Profound understanding of pericyte roles at the BBB and underlying mechanisms for the regulation of BBB transport are important as a potential strategy to improve drug delivery in treatment of CNS disorders. The aim of the present study was to investigate pericyte role in the rate of small-molecular drug transport across the BBB, by examining three model compounds in a pericyte-deficient state. Diazepam, oxycodone and paliperidone were selected for this purpose based on utilization of different transport mechanisms at the BBB. The rate of brain uptake was assessed by implementing the trans-cardiac in situ brain perfusion technique. Radiolabeled 14C-sucrose was used as a vascular marker. Pericyte-deficient mice (Pdgfb(ret/ret)) exhibited significantly larger brain vascular volumes (V-vasc) 1.72 +/- 0.13 mL/100 g brain, compared to littermate controls with normal pericyte coverage (Pdgfb(ret/+)) 1.15 +/- 0.13 mL/100 g brain (p < 0001). However, the unidirectional transfer coefficient Kin, which describes the rate of brain uptake, was not different between Pdgfb(ret/ret) and Pdgfb(ret/+) mice for all three tested compounds. Taken together the present results indicate no pericyte influence in the rate of small-molecular drug transport at the BBB, despite the larger brain vascular volumes that were observed in a pericyte-deficient state.

Place, publisher, year, edition, pages
2018. Vol. 124, p. 182-187
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-345939DOI: 10.1016/j.ejps.2018.08.009ISI: 000447981200018PubMedID: 30098392OAI: oai:DiVA.org:uu-345939DiVA, id: diva2:1189912
Funder
EU, FP7, Seventh Framework Programme, 317250Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2019-01-07Bibliographically approved
In thesis
1. Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier: Implications for Therapy of Neurodegenerative Diseases
Open this publication in new window or tab >>Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier: Implications for Therapy of Neurodegenerative Diseases
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood-brain barrier (BBB) represents a complex interface between the brain parenchyma and systemic blood circulation, strictly controlling exchange of substances between the two sites. Pericytes are mural cells located on the abluminal membrane of the brain endothelium, involved in BBB formation and maintenance. Previous studies have implied that pericyte-deficiency causes alterations in BBB integrity for larger molecules, mainly by upregulated transcytosis pathways.

 The aim of the thesis was to examine the role of pericytes for small-molecular drug transport across the BBB, by providing a closer insight into different aspects of transport in a pericyte-deficient state. PDGF-B retention motif knockout mice were used as a well-established pericyte-deficient model. Small-molecular drugs, namely diazepam, digoxin, imatinib, levofloxacin, oxycodone and paliperidone were selected based on utilization of different BBB transport mechanisms. Surprisingly, the extent of BBB transport expressed as the unbound brain-to-unbound plasma partition coefficients indicated no difference between pericyte-deficient and control mice for all tested drugs. In addition, no difference was observed in the rate of BBB transport estimated by trans-cardiac in situ brain perfusion experiments. These results imply preserved BBB features in terms of tight junctions that limit para-cellular transport, as well as unaltered transporter functionality and expression. Thus, BBB aspects relevant for small-molecular drug transport seem to be maintained regardless of pericyte presence at the BBB. In addition, data from proteome and transcriptome analysis of the brain microvasculature fragments were in line with these findings, showing no difference in major transporter expressions at the BBB in pericyte-deficient mice. Finally, experiments with tyrosine kinase (TK) inhibitors suggested a potential relevance of the imatinib-like TK target profiles for the stabilization of compromised BBB integrity in pericyte-deficiency.

 In conclusion, the present thesis work provided comprehensive insight into pharmacokinetics of small-molecular drugs in a pericyte-deficient state. It represents an important initial platform for future extensive investigations of BBB transport in pericyte-deficiency, towards the ultimate goal of developing novel therapeutics for the treatment of different neurodegenerative diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 250
Keywords
Blood-brain barrier, pericytes, pericyte-deficiency, pharmacokinetics, small-molecular drugs, drug distribution, transporters, P-glycoprotein, tyrosine kinase inhibitors
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-345949 (URN)978-91-513-0271-3 (ISBN)
Public defence
2018-05-04, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2018-04-10 Created: 2018-03-13 Last updated: 2018-04-24

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