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Hammarlund-Udenaes, MargaretaORCID iD iconorcid.org/0000-0002-9181-1321
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Publications (10 of 78) Show all publications
Gustafsson, S., Lindström, V., Ingelsson, M., Hammarlund-Udenaes, M. & Syvänen, S. (2018). Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology. Neuropharmacology, 128, 482-491
Open this publication in new window or tab >>Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology
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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
Keywords
Blood-brain barrier, Pharmacokinetics, Drug transport, Disease, Amyloid beta, Alpha-synuclein
National Category
Neurology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-340458 (URN)10.1016/j.neuropharm.2017.08.002 (DOI)000418977200043 ()28797721 (PubMedID)
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-03-27Bibliographically approved
Mihajlica, N., Betsholtz, C. & Hammarlund-Udenaes, M. (2018). Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier. European Journal of Pharmaceutical Sciences, 122, 77-84
Open this publication in new window or tab >>Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier
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
Keywords
Pericytes, Blood-brain barrier, Small-molecular drugs, Drug partitioning, Extent of transport, Unbound drug fractions
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-345932 (URN)10.1016/j.ejps.2018.06.018 (DOI)000439564000009 ()29933077 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-10-17Bibliographically approved
Gustafsson, S., Eriksson, J., Syvänen, S., Eriksson, O., Hammarlund-Udenaes, M. & Antoni, G. (2017). Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations. NeuroImage, 155, 177-186
Open this publication in new window or tab >>Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, p. 177-186Article in journal (Refereed) Published
Abstract [en]

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 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min 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, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332421 (URN)10.1016/j.neuroimage.2017.04.068 (DOI)000405460900015 ()28467891 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2018-03-27Bibliographically approved
Greenwood, J., Hammarlund-Udenaes, M., Jones, H. C., Stitt, A. W., Vandenbrouke, R. E., Romero, I. A., . . . Khrestchatisky, M. (2017). Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017. Fluids and Barriers of the CNS, 14, Article ID 31.
Open this publication in new window or tab >>Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017
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2017 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 31Article, review/survey (Refereed) Published
Abstract [en]

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.

Keywords
Blood-brain barrier, Blood-CSF barrier, Blood-retinal barrier, Neuroinflammation, Viral vectors, Drug delivery, Antibody therapy, MicroRNA, Liposomal technology, Protein capsules
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-346611 (URN)10.1186/s12987-017-0079-9 (DOI)000414755100001 ()
Note

Correction in: Fluids and Barriers of the CNS, 2018, 15:3

https://doi.org/10.1186/s12987-017-0086-x

Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-04-26Bibliographically approved
Chen, X., Keep, R. F., Liang, Y., Zhu, H.-J., Hammarlund-Udenaes, M., Hu, Y. & Smith, D. E. (2017). Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study. Biochemical Pharmacology, 131, 89-97
Open this publication in new window or tab >>Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study
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2017 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 131, p. 89-97Article in journal (Refereed) Published
Abstract [en]

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a beta-lactam antibiotic and PEN 2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4 h at 0.15 mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability surface area experiment was also performed in which 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keywords
Microdialysis, Peptide transporter 2, Blood-cerebrospinal fluid barrier, Cefadroxil, Brain extracellular fluid
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-321784 (URN)10.1016/j.bcp.2017.02.005 (DOI)000399256700008 ()28192085 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2018-01-13Bibliographically approved
Hammarlund-Udenaes, M. (2017). Microdialysis as an Important Technique in Systems Pharmacology: a Historical and Methodological Review. AAPS Journal, 19(5), 1294-1303
Open this publication in new window or tab >>Microdialysis as an Important Technique in Systems Pharmacology: a Historical and Methodological Review
2017 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 19, no 5, p. 1294-1303Article, review/survey (Refereed) Published
Abstract [en]

Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

Keywords
microdialysis, pharmacodynamics, pharmacokinetics, pharmacology, recovery methods, systems
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-345884 (URN)10.1208/s12248-017-0108-2 (DOI)000408407300006 ()28762127 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13Bibliographically approved
Kusuhara, H., Obach, R. S., Rostami-Hodjegan, A., Pang, K. S., Hammarlund-Udenaes, M., Derendorf, H., . . . Terasaki, T. (2017). Professor Yuichi Sugiyama: A Brilliant, Creative, Amicable, Charming, and Humorous Pharmaceutical Scientist. Journal of Pharmaceutical Sciences, 106(9), 2188-2194
Open this publication in new window or tab >>Professor Yuichi Sugiyama: A Brilliant, Creative, Amicable, Charming, and Humorous Pharmaceutical Scientist
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2017 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2188-2194Article in journal, Editorial material (Other academic) Published
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-345604 (URN)10.1016/j.xphs.2017.04.072 (DOI)000417339900002 ()28479350 (PubMedID)
Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-09Bibliographically approved
Loryan, I., Hoppe, E., Hansen, K., Held, F., Kless, A., Linz, K., . . . Hammarlund-Udenaes, M. (2017). Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development. Molecular Pharmaceutics, 14(12), 4362-4373
Open this publication in new window or tab >>Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4362-4373Article in journal (Refereed) Published
Abstract [en]

Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.

Keywords
brain slice, drug induced phospholipidosis, intracellular concentration, lung slice, pharmacokinetics, unbound drug
National Category
Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-342077 (URN)10.1021/acs.molpharmaceut.7b00480 (DOI)000417342400025 ()29099189 (PubMedID)
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-03-08Bibliographically approved
Agrawal, M., Ajazuddin, A., Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., . . . Alexander, A. (2017). Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease. Journal of Controlled Release, 260, 61-77
Open this publication in new window or tab >>Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease
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2017 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 260, p. 61-77Article, review/survey (Refereed) Published
Abstract [en]

In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.

Keywords
Alzheimer, beta amyloid, Liposome, Lactoferrin, Transferrin, Glutathione
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-335804 (URN)10.1016/j.jconrel.2017.05.019 (DOI)000405482100006 ()28549949 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-02-21Bibliographically approved
Chen, X., Slättengren, T., de Lange, E. C. M., Smith, D. E. & Hammarlund-Udenaes, M. (2017). Revisiting atenolol as a low passive permeability marker. Fluids and Barriers of the CNS, 14, Article ID 30.
Open this publication in new window or tab >>Revisiting atenolol as a low passive permeability marker
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2017 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 30Article in journal (Refereed) Published
Abstract [en]

Background: Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB.

Methods: To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis.

Results: The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., -K-p,K-uu,K-brain) was 3.5% +/- 0.4%, a value much less than unity. The unbound volume of distribution in brain -(V-u,V- brain) of S-atenolol was also calculated as 0.69 +/- 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction -(f(u, brain)) of 0.88 +/- 0.07.

Conclusions: It is concluded, based on -K-p,K-uu,K-brain being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.

Keywords
Atenolol, Blood-brain barrier, Microdialysis, Unbound equilibrium partition coefficient (K-p, K-uu, K-brain), Unbound volume of distribution in brain (V-u, V-brain), Passive permeability, Transporters, Pharmacokinetics, Lipophilicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-341367 (URN)10.1186/s12987-017-0078-x (DOI)000414175000001 ()29089037 (PubMedID)
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9181-1321

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