Assessment of the blood–brain barrier in CNS drug discovery

Jeffrey, Phil; Summerfield, Scott

doi:10.1016/j.nbd.2009.07.033

Cited by 99 publications

(63 citation statements)

References 42 publications

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“…On one side there are a large number of neurological disorders including cerebral ischemia, brain trauma and tumors, neurodegenerative disorders, in which the permeability of the BBB is increased. On the other hand due to the relative impermeability of the barrier many drugs are unable to reach the CNS in therapeutically relevant concentration, making the BBB one of the major hindrances in the treatment of CNS disorders [30]. Most of the native opioid peptides in general have a limited in vivo efficacy, due to their poor metabolic stability and limited delivery to the CNS [31].…”

Section: Blood-brain Barrier (Bbb) and Its Significancementioning

confidence: 99%

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Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

Mallareddy

Borics

Keresztes

et al. 2011

Pharmacological Reports

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Section: Blood-brain Barrier (Bbb) and Its Significancementioning

confidence: 99%

“…The BBB plays a significant role in the treatment of CNS disorders [30]. It is widely accepted that the mediation of analgesic effects occurs within the CNS, therefore opioid peptides should be able to cross the BBB intact.…”

Section: In Vitro Bbb Permeability Of Em-2 Analogues By Brain Capillamentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

Mallareddy

Borics

Keresztes

et al. 2011

Pharmacological Reports

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“…Most large molecules such as proteins cannot cross the BBB; therefore brain is most resistant to bacterial infections normally (Banks and Erickson 2010). However this characteristic also weakened the efficiency of drug delivery into the brain, as antibiotics and antibodies are too large to pass the BBB (Jeffrey and Summerfield 2010). Targeted brain drug delivery after vein administration therefore requires the drug molecules to cross BBB efficiently to reach the effective concentration.…”

Section: Different Routes For Brain Drug Delivery With Nanotechnologymentioning

confidence: 99%

Recent advances in nanotechnology based drug delivery to the brain

et al. 2010

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Drug delivery into the brain was difficult due to the existence of blood brain barrier, which only permits some molecules to pass through freely. In past decades, nanotechnology has enabled many technical advances including drug delivery into the brain with high efficiency and accuracy. In the present paper, we summarize recent important advances in employing nanotechnology for drug delivery to the brain as well as controlled drug release.

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“…In recent years, much attention has been given to blood-brain barrier (BBB) permeability, as this is assumed to be the main determinant of CNS exposure (4)(5)(6)(7)(8)(9). However, even though BBB permeability is a very important determinant, it is not the only relevant process.…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling to Investigate Regional Brain Distribution Kinetics in Rats

Westerhout

Ploeger²,

Smeets³

et al. 2012

AAPS J

105

122

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Abstract. One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF LV , and CSF CM indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC 0−240 ratios of 121%, 28%, and 35% for brain ECF, CSF LV , and CSF CM , respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations.

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Assessment of the blood–brain barrier in CNS drug discovery

Cited by 99 publications

References 42 publications

Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

Recent advances in nanotechnology based drug delivery to the brain

Physiologically Based Pharmacokinetic Modeling to Investigate Regional Brain Distribution Kinetics in Rats

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