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Exploring Factors Causing Low Brain penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling
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 Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD)
2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 4, 1258-1266 p.Article in journal (Refereed) Published
Abstract [en]

To advance the development of peptide analogues for improved treatment of pain, we need to learn more about the blood brain barrier transport of these substances. A low penetration into the brain, with an unbound brain to blood ratio, K-p,K-uu, of 0.08, is an important reason for the lack of effect of the enkephalin analogue DAMGO (H-Tyr-D-Ala-Gly-MePhe-Gly-ol) according to earlier findings. The aim of this study was to investigate the role of efflux transporters, metabolism in the brain, and/or elimination through interstitial fluid bulk flow for the brain exposure of DAMGO. The in vivo brain distribution of DAMGO was evaluated using microdialysis in the rat. Data were analyzed with population modeling which resulted in a clearance into the brain of 1.1 and an efflux clearance 14 mu L/min/g_brain. The efflux clearance was thus much higher than the bulk flow known from the literature. Coadministration with the efflux transporter inhibitors cyclosporin A and elacridar in vivo did not affect K-p,K-uu. The permeability of DAMGO in the Caco-2 assay was very low, of the same size as mannitol. The efflux ratio was <2 and not influenced by cyclosporin A or elacridar. These results indicate that the well-known efflux transporters Pgp and Bcrp are not responsible for the higher efflux of DAMGO, which opens up for an important role of other transporters at the BBB.

Place, publisher, year, edition, pages
2016. Vol. 13, no 4, 1258-1266 p.
Keyword [en]
CNS, blood-brain barrier, microdialysis, permeability, Pgp, population modeling, NONMEM, elacridar, cyclosporine A, efflux, pharmacokinetics
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-267592DOI: 10.1021/acs.molpharmaceut.5b00835ISI: 000373550600007PubMedID: 26898546OAI: oai:DiVA.org:uu-267592DiVA: diva2:873719
Funder
Swedish Research Council
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved
In thesis
1. Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier: Exemplified with the Opioid Peptide DAMGO
Open this publication in new window or tab >>Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier: Exemplified with the Opioid Peptide DAMGO
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The use of nanocarriers is an intriguing approach in the development of efficacious treatment for brain disorders. The aim of the conducted research was to evaluate and quantify the impact of a liposomal nanocarrier formulation on the brain drug delivery. A novel approach for investigating the blood-brain barrier transport of liposomal DAMGO is presented, including in vivo microdialysis in rat, a high quality LC-MS/MS bioanalytical method and pharmacokinetic model analysis of the data. Factors limiting the brain distribution of the free peptide DAMGO were also investigated. Microdialysis, in combination with plasma sampling, made it possible to separate the released drug from the encapsulated and to quantify the active substance in both blood and brain interstitial fluid over time.

The opioid peptide DAMGO entered the brain to a limited extent, with a clearance out of the brain 13 times higher than the clearance into the brain. The brain to blood ratio of unbound drug was not affected when the efflux transporter inhibitors cyclosporine A and elacridar were co-administered with DAMGO. Nor was the transport affected in the in vitro Caco-2 assay using the same inhibitors. This indicates that DAMGO is not transported by P-glycoprotein (Pgp) or breast cancer resistant protein (Bcrp). The blood-brain barrier transport was significantly increased for DAMGO when formulated in liposomes, resulting in 2-3 fold higher brain to blood ratio of unbound DAMGO. The increased brain delivery was seen both for glutathione tagged PEGylated liposomes, as well as for PEGyalted liposomes without specific brain targeting. The improvement in brain delivery was observed only when DAMGO was encapsulated into the liposomes, thus excluding any effect of the liposomes themselves on the integrity of the blood-brain barrier. Modeling of the data provided additional mechanistic understanding of the brain uptake, showing that endocytosis or transcytosis of intact liposomes across the endothelial cell membranes were unlikely. A model describing fusion of the liposomes with the luminal membrane described the experimental data the best.

In conclusion, the studies presented in this thesis all contribute to an increased understanding of how to evaluate and improve brain delivery of CNS active drugs and contribute with important insights to the nanocarrier field.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 208
Keyword
blood-brain barrier, liposomes, nanocarriers, brain delivery, pharmacokinetics, modeling and simulation, microdialysis, opioid peptide, DAMGO, LC-MS/MS
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-267599 (URN)978-91-554-9428-5 (ISBN)
Public defence
2016-01-15, B42, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-12-21 Created: 2015-11-24 Last updated: 2016-01-13

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Lindqvist, AnnikaJönsson, SivHammarlund-Udenaes, Margareta

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