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Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier
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. 122, p. 77-84Article in journal (Refereed) Published
Abstract [en]

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfb(ret/ret) mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (K-p,K-brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (f(u,brain)) and plasma (f(u,plasma)). This enabled estimation of unbound drug partitioning coefficients (K-p,K-uu,K-brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfb(ret/ret) mice as reflected in K-p,K-brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar K-p,K-uu,K-brain Values in Pdgfb(ret/ret) and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 122, p. 77-84
Keywords [en]
Pericytes, Blood-brain barrier, Small-molecular drugs, Drug partitioning, Extent of transport, Unbound drug fractions
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-345932DOI: 10.1016/j.ejps.2018.06.018ISI: 000439564000009PubMedID: 29933077OAI: oai:DiVA.org:uu-345932DiVA, id: diva2:1189910
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-10-17Bibliographically 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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Mihajlica, NebojsaBetsholtz, ChristerHammarlund-Udenaes, Margareta

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