Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier

Gratton, J; Abraham, Michael H.; Bradbury, M. W. B.; Chadha, Harpreet S.

doi:10.1111/j.2042-7158.1997.tb06072.x

Cited by 133 publications

(99 citation statements)

References 25 publications

(15 reference statements)

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“…The main limitation is that K p is not a good parameter for characterizing the brain penetration as discussed above. To address the limitation of the logK p model, Gratton et al (1997) and Liu et al (2004) developed a BBB permeability (logPS) model using the data generated with the in situ brain perfusion method. The logPS model may be used in conjunction with in vivo logPS.…”

Section: What In Silico Bbb Models Need To Be Developed?mentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

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This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development. Brain penetration kinetics can be described by the extent and time to reach brain equilibrium. The extent is defined as the ratio of free brain concentration to free plasma concentration at steady state. For all central nervous system (CNS) drug discovery programs, optimization of the extent of brain penetration should focus on designing and selecting compounds having low efflux transport at the blood-brain barrier (BBB). The time to reach brain equilibrium is determined by both BBB permeability and brain tissue binding. Rapid brain penetration can be achieved by increasing passive permeability and reducing brain tissue binding. Although many drug transporters have been identified at the BBB, the available literature demonstrates only the in vivo functional importance of P-glycoprotein (P-gp) in limiting brain penetration of its substrates. Drug-drug interactions mediated by P-gp at the BBB are possible due to inhibition or induction of P-gp. For newly identified drug transporters at the BBB, more research is needed to reveal their in vivo significance. We propose the following strategies for addressing drug transporters at the BBB. 1) Drug discovery screens should be used to eliminate good P-gp substrates for CNS targets. Special consideration could be given to moderate P-gp substrates as potential CNS drugs based on a high unmet medical need and the presence of a large safety margin. 2) Selection of P-gp substrates as drug candidates for non-CNS targets can reduce their CNS-mediated side effects.Brain is separated from the systemic circulation by two barriers: the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is composed of cerebral endothelial cells that differ from those in the rest of the body by the presence of extensive tight junctions, absence of fenestrations, and sparse pinocytotic vesicular transport. The BCSFB is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. The BBB and BCSFB exhibit very low paracellular permeability and express multiple drug transporters. These characteristics restrict the entry of hydrophilic compounds or efflux transport substrates into brain (Davson and Segal, 1995). In this review, we will summarize recent published data relevant to assess drug brain penetration and present the authors' opinions on how to effectively address BBB issues in drug discovery and development.

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Section: What In Silico Bbb Models Need To Be Developed?mentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

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“…3,4 The BBB penetration potential of drug candidates may be assessed by various in silico, in vivo, and in vitro methods. In silico approaches include the determination of physicochemical properties such as octanol-water partition coefficient (log P), 5 hydrogen-bonding potential (∆ log P), 6 molecular polar surface area (PSA), 7 linear free energy, 8,9 and surface tension. 10,11 In vivo biological approaches include microdialysis, 12,13 cerebrospinal fluid sampling, 12,14 autoradiography, 15 nuclear magnetic resonance, 16 and positron emission spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

Yoon¹,

Kim²,

Shin³

et al. 2006

SLAS Discovery

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The chromatographic capacity factors (k IAM ) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (IAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The k IAM was determined using the mobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (k IAM /MW n ). The correlation between k IAM /MW n and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro prediction method was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r = 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility. (Journal of Biomolecular

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“…Several studies have been reported to determine PS values using the brain perfusion method and to examine the correlation of logPS and physical properties. Smith and Takasato (1986) and Gratton et al (1997) demonstrated that the partitioning coefficient (logP) correlated with BBB permeability. Murakami et al (2000) observed a correlation of log(D ⅐ MW Ϫ0.5 ) and logPS for a dozen compounds.…”

mentioning

confidence: 99%

“…One approach is to use computational methods that can be applied to virtual libraries, allowing rapid and costeffective elimination of poor candidates, or to rank them even before synthesis, when traditional medicinal chemistry approaches are used. Many computational models using only two-dimensional and threedimensional structure descriptors have been proposed to predict the logBB and logPS (Levin, 1980;Lombardo et al, 1996;Gratton et al, 1997;Clark, 1999;Lobell et al, 2002; Norinder and Haeberlein, 1 Abbreviations used are: BBB, blood-brain barrier; BB, brain-blood concentration ratio; PS, permeability-surface area product; LFER, linear free energy relationship; DPDPE, 2,5-D-penicillamine enkephalin; SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride; NFPS,propyl]sarcosine; HPLC, high-pressure liquid chromatography; MS/MS, tandem mass spectrometry; TPSA, topological polar surface area; vsa_base, van der Waals surface area of the basic atoms; P-gp, P-glycoprotein; CP-141938, N-{4-methoxy-3-[(2-phenyl-piperadin-3ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide.…”

mentioning

confidence: 99%

Development of a Computational Approach to Predict Blood-Brain Barrier Permeability

Liu

Tu²,

Kelly³

et al. 2004

Drug Metab Dispos

216

174

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The objectives of this study were to generate a data set of bloodbrain barrier (BBB) permeability values for drug-like compounds and to develop a computational model to predict BBB permeability from structure. The BBB permeability, expressed as permeabilitysurface area product (PS, quantified as logPS), was determined for 28 structurally diverse drug-like compounds using the in situ rat brain perfusion technique. A linear model containing three descriptors, logD, van der Waals surface area of basic atoms, and polar surface area, was developed based on 23 compounds in our data set, where the penetration across the BBB was assumed to occur primarily by passive diffusion The blood-brain barrier (BBB 1 ) consists of a continuous layer of endothelial cells joined by tight junctions at the cerebral vasculature. It represents a physical and enzymatic barrier to restrict and regulate the penetration of compounds into and out of the brain and maintain the homeostasis of the brain microenvironment (Davson and Segal, 1995). Brain penetration is essential for compounds where the site of action is within the central nervous system, whereas BBB penetration needs to be minimized for compounds that target peripheral sites to reduce potential central nervous system-related side effects. Therefore, it is critical during the drug discovery phase to select compounds that have appropriate brain penetration properties. Brain penetration is commonly assessed by two experimental approaches, namely equilibrium distribution between brain and blood and BBB permeability. The equilibrium distribution is defined as the ratio of concentrations in brain and blood (BB, quantified as logBB). LogBB is determined at

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Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier

Cited by 133 publications

References 25 publications

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

Development of a Computational Approach to Predict Blood-Brain Barrier Permeability

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