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Cited by 378Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsCerebrospinal fluid and hydrocephalus

Macromolecular permeability across the blood-nerve and blood-brain barriers.

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Poduslo, J F, Curran, G L, Berg, C T·1994·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.91.12.5705PMC PMC44065
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Abstract

The permeability of insulin (Ins), nerve growth factor (NGF), albumin (Alb), transferrin (Trf), and IgG across the blood-nerve barrier (BNB) and blood-brain barrier (BBB) in normal adult rats was quantified by measuring the (permeability coefficient x surface area) product (PS) with the i.v. bolus-injection technique in the cannulated brachial vein and artery using radioiodinated proteins. The PS values of the BNB for IgG and Alb were low: 0.079 +/- 0.029 x 10(-6) and 0.101 +/- 0.088 x 10(-6) ml.g-1.s-1, (mean +/- SD, respectively). The PS values for NGF and Trf were 16.1-fold and 25.5-fold higher than for Alb. The PS for Ins across the BNB was 33.190 +/- 2.053 x 10(-6) ml.g-1.s-1--a remarkable 329-fold increase compared with Alb. The PS values of the BBB for IgG and Alb in different brain regions were all low, from 0.028 +/- 0.017 to 0.151 +/- 0.035 x 10(-6) ml.g-1.s-1 (mean +/- SD). NGF and Trf had comparable PS values from 13- to 32-fold higher than for Alb, except for the brain stem, where the PS for Trf was 66-fold higher than for Alb. The mean PS for Ins across the BBB ranged from 15.78 +/- 5.45 x 10(-6) ml.g-1.s-1 for the cortex to 22.62 +/- 7.50 x 10(-6) ml.g-1.s-1 for the brain stem--again a remarkable 105- to 390-fold increase relative to Alb. Because reliable PS measurements were obtained for all proteins tested, the BBB and BNB cannot be considered impermeable to proteins--a concept that has plagued brain- and nerve-barrier research. The low PS values for IgG and Alb indicate low rates of transfer; however, Alb, in particular, is the major protein of endoneurial and ventricular fluid, which suggests that these PS values may be significant. Ins had the highest PS values, which likely reflect the mechanism of transport across the barriers--that is, receptor-mediated transport. Because NGF and Trf had PS values 13- to 66-fold higher than for Alb, whether this reflects receptor-mediated uptake, adsorptive-mediated transcytosis, or some other mechanism is unclear. That the PS values for NGF and Trf differ from Alb and IgG clearly suggests, however, a different uptake mechanism. Finally, the remarkably high PS values for Ins across the BBB and BNB identify this protein and its putative receptor on capillary endothelial cells as a potential target for drug delivery into the central and peripheral nervous systems.

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Crossref · 10.1073/pnas.91.12.5705

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  • mAbs exhibit limited distribution to the brain, with mAb concentrations determined to be 0.1-0.2% and 0.02% of the steady-state circulating mAb concentration in rodents and cynomolgus monkey, respectively.

    “mAbs exhibit limited distribution to the brain, and mAb concentrations was determined to be 0.1–0.2 % and 0.02 % of the steady‐state circulating mAb concentration in rodents and cynomolgus monkey, respectively.92, 93”

    From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [92]

  • The PK of the anti-Her2/CD3 T cell-dependent bispecific (TDB) antibody in rats demonstrated similar clearance and half-life as trastuzumab.

    “the PK of the anti‐Her2/CD3T cell‐dependent bispecific (TDB) antibody in rats demonstrated similar clearance and half‐life as trastuzumab.92”

    From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [92]

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Authors
Poduslo, J. F., Curran, G. L., & Berg, C. T.
Affiliations
Mayo Clinic (US)
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1994-06-07
Volume
91
Issue
12
Pages
5705-5709
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.91.12.5705
PMC
PMC44065
OpenAlex
W2071079524
Cited by
377
References
82
Citations by year
2026: 10 · 2025: 16 · 2024: 18 · 2023: 24 · 2022: 16 · 2021: 16 · 2020: 32 · 2019: 16 · 2018: 20 · 2017: 16 · 2016: 14 · 2015: 10 · 2014: 9 · 2013: 12 · 2012: 19
FWCI
6.26
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Keywords
blood-nerve barrier, blood-brain barrier, macromolecule permeability, protein permeability, insulin, nerve growth factor, transferrin, IgG, albumin, permeability coefficient, brain regions, brainstem, ventricular fluid, radioiodinated proteins, rats
MeSH terms
Albumins, Animals, Blood-Brain Barrier, Brain, Endocytosis, Insulin, Male, Metabolic Clearance Rate, Nerve Growth Factors, Permeability, Transferrin, Rats, Sprague-Dawley, Rats

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