Pharmacokinetics of CNS Penetration

Reichel, Andreas

doi:10.1002/9781118788523.ch2

Cited by 7 publications

(4 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This relation implies that the larger volumes of fluid in the intracellular spaces and the major blood vessels and cerebral spinal fluid (CSF) spaces are relatively constant across our sample space (O’Brien and Sampson 1965 , Siegel et al 1999 , Elkin et al 2010 , Keep et al 2012 , Jessen et al 2015 , Reichel 2015 , Gottschalk et al 2021 ). Then, for the modulus of E given by equation ( 7 ), assuming a = 0.05 as a benchmark, and E 0 = 13.3 kPa, we can plot the modulus as a function of water content, with χ varying as the parametric parameter between 0.94 < χ < 1.06.…”

Section: Resultsmentioning

confidence: 99%

Fluid compartments influence elastography of the aging mouse brain

Rolland

Song

et al. 2023

Phys. Med. Biol.

View full text Add to dashboard Cite

Objective: Elastography of the brain has the potential to reveal subtle but clinically important changes in the structure and composition as a function of age, disease, and injury. Approach: In order to quantify the specific effects of aging on mouse brain elastography, and to determine the key factors influencing observed changes, we applied optical coherence tomography reverberant shear wave elastography at 2000 Hz to a group of wild-type healthy mice ranging from young to old age. Main Results: We found a strong trend towards increasing stiffness with age, with an approximately 30% increase in shear wave speed from 2 months to 30 months within this sampled group. Furthermore, this appears to be strongly correlated with decreasing measures of whole brain fluid content, so older brains have less water and are stiffer. Rheological models are applied, and the strong effect is captured by specific assignment of changes to the glymphatic compartment of the brain fluid structures along with a correlated change in the parenchymal stiffness. Significance: Short-term and longer-term changes in elastography measures may provide a sensitive biomarker of progressive and fine-scale changes in the glymphatic fluid channels and parenchymal components of the brain.

show abstract

Section: Resultsmentioning

confidence: 99%

Fluid compartments influence elastography of the aging mouse brain

Rolland

Song

et al. 2023

Phys. Med. Biol.

View full text Add to dashboard Cite

show abstract

“…The speed of blood flow within the blood vessels is also critical for transport. Cerebral blood flow, in concert with the permeability of the compound, directly relate to the rate of CNS penetration ( Reichel, 2015 ). For example, gases such as carbon dioxide, oxygen, and volatile anesthetics diffuse rapidly into the brain and are limited primarily by the cerebral blood flow rate.…”

Section: What Constitutes the Brain Barriers?mentioning

confidence: 99%

The development and function of the brain barriers – an overlooked consideration for chemical toxicity

Bell

O’Shaughnessy²

2022

Front. Toxicol.

View full text Add to dashboard Cite

It is well known that the adult brain is protected from some infections and toxic molecules by the blood-brain and the blood-cerebrospinal fluid barriers. Contrary to the immense data collected in other fields, it is deeply entrenched in environmental toxicology that xenobiotics easily permeate the developing brain because these barriers are either absent or non-functional in the fetus and newborn. Here we review the cellular and physiological makeup of the brain barrier systems in multiple species, and discuss decades of experiments that show they possess functionality during embryogenesis. We next present case studies of two chemical classes, perfluoroalkyl substances (PFAS) and bisphenols, and discuss their potential to bypass the brain barriers. While there is evidence to suggest these pollutants may enter the developing and/or adult brain parenchyma, many studies suffer from confounding technical variables which complicates data interpretation. In the future, a more formal consideration of brain barrier biology could not only improve understanding of chemical toxicokinetics but could assist in prioritizing environmental xenobiotics for their neurotoxicity risk.

show abstract

“…While it is nonsaturable, it depends significantly on drug physico-chemical properties, such as low molecular weight, and lipid solubility. While higher lipid solubility leads to better BBB penetration [ 8 ], it also leads to an unfavorable increase in oxidative metabolism and volume of distribution [ 8 ]. Therefore, the effects of increasing lipophilicity on BBB penetration must be balanced in light of membrane permeability and metabolism [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Strategies for Enhancing the Permeation of CNS-Active Drugs through the Blood-Brain Barrier: A Review

2018

View full text Add to dashboard Cite

Background: The blood brain barrier (BBB) is a dynamic and functional structure which poses a vast challenge in the development of drugs acting on the central nervous system (CNS). While most substances are denied BBB crossing, selective penetration of substances mainly occurs through diffusion, carrier mediated transport, or receptor mediated transcytosis. Methods: Strategies in enhancing BBB penetration have been reviewed and summarized in accordance with their type of formulation. Highlights in monoclonal antibodies, peptide-vectors, nanoparticles, and simple prodrugs were included. Conclusion: Nanoparticles and simple prodrugs, for example, can be used for efficient BBB penetration through inhibition of efflux mechanisms, however, monoclonal antibodies are the most promising strategy in BBB penetration. Close follow-up of future development in this area should confirm our expectation.

show abstract

Pharmacokinetics of CNS Penetration

Cited by 7 publications

References 112 publications

Fluid compartments influence elastography of the aging mouse brain

Fluid compartments influence elastography of the aging mouse brain

The development and function of the brain barriers – an overlooked consideration for chemical toxicity

Strategies for Enhancing the Permeation of CNS-Active Drugs through the Blood-Brain Barrier: A Review

Contact Info

Product

Resources

About