Blood–brain barrier permeability considerations for CNS-targeted compound library design

Hitchcock, Stephen A.

doi:10.1016/j.cbpa.2008.03.019

Cited by 89 publications

(58 citation statements)

References 32 publications

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“…This network of specialized endothelial cells inhibits transcellular passage by low pinocytotic activity and inhibits paracellular diffusion by an elaborate network of tight junctions (Kniesel and Wolburg, 2000). Most attempts have focused on developing small-molecule drugs that can be optimized to facilitate their transport into the CNS (Hitchcock, 2008). Despite the many successes, many targets have been intractable to small-molecule development.…”

Section: Downloaded Frommentioning

confidence: 99%

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Pepinsky¹,

Shao²,

Ji³

et al. 2011

J Pharmacol Exp Ther

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LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.

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Section: Downloaded Frommentioning

confidence: 99%

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Pepinsky¹,

Shao²,

Ji³

et al. 2011

J Pharmacol Exp Ther

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“…It is generally accepted that only small molecules with low molecular mass (Ͻ450 Da) and high lipid solubility permeate the healthy BBB by a passive transcellular process (13). The tight junctions of the interendothelial domains restrict the passage of large hydrophilic molecules through the paracellular route (14), and this is expected to be the main reason for the low BBB penetration of colistin observed (given a molecular mass of 1,163 Da) (19).…”

mentioning

confidence: 99%

Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

Jin

Nation

et al. 2011

Antimicrob Agents Chemother

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The aim of this study was to investigate the factors limiting the blood-brain barrier (BBB) transport of colistin in healthy mice and to assess the impact of systemic inflammation on the transport of this antibiotic across the BBB. Colistin sulfate (40 mg/kg) was administered subcutaneously to Swiss outbred mice as single and multiple doses to determine any relationship between brain uptake and plasma concentrations of colistin. To assess the effect of P-glycoprotein (P-gp) on BBB transport, colistin sulfate (5 mg/kg) was concomitantly administered intravenously with PSC833 or GF120918 (10 mg/kg). Systemic inflammation was induced by three intraperitoneal injections of lipopolysaccharide (LPS; 3 mg/kg), and BBB transport of colistin was subsequently measured following subcutaneous administration and by an in situ brain perfusion. The brain uptake of colistin was low following single and multiple subcutaneous doses, with brain-to-plasma concentration ratios ranging between 0.021 and 0.037, and this was not significantly enhanced by coadministration of GF120918 or PSC833 (P > 0.05). LPS significantly increased the brain uptake of subcutaneously administered colistin with area under the brain concentration time curve (AUC brain ) values of 11.7 ؎ 2.7 g ⅐ h/g and 4.0 ؎ 0.3 g ⅐ h/g for LPS-and saline-treated mice, respectively (mean ؎ standard deviation). Similarly, in situ perfusion of colistin led to higher antibiotic brain concentrations in LPS-treated animals than in saline-treated animals, with colistin brain-to-perfusate concentration ratios of 0.019 ؎ 0.001 and 0.014 ؎ 0.001, respectively. This study demonstrates that the BBB transport of colistin is negligible in healthy mice; however, brain concentrations of colistin can be significantly enhanced during systemic inflammation, as might be observed in infected patients.

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“…Data are presented as means Ϯ standard deviations (n ϭ 4). (9). Third, like many large cationic compounds, colistin may be actively excluded from the brain parenchyma by active efflux systems, such as P-glycoprotein (23).…”

Section: Resultsmentioning

confidence: 99%

Brain Penetration of Colistin in Mice Assessed by a Novel High-Performance Liquid Chromatographic Technique

Jin

Nation

et al. 2009

Antimicrob Agents Chemother

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A sensitive and reliable liquid chromatographic method was developed and validated for the determination of colistin concentrations in mouse brain homogenate. With a mobile phase consisting of acetonitrile-tetrahydrofuran-water (50:25:25 [vol/vol]) at a flow rate of 1 ml/min, a linear correlation between peak area and colistin concentration was observed over the concentration range of 93.8 to 3,000 ng/g in brain tissue (R 2 > 0.994). Intra-and interday coefficients of variation were 5.1 to 8.3% and 5.8 to 8.5%, respectively, and the recovery ranged from 85% to 94%. This assay was then utilized to determine the amount of colistin that permeated the blood-brain barrier over a 2-h period following bolus intravenous administration of colistin sulfate to mice. After a single dose of 5 mg/kg of body weight to mice, brain homogenate concentrations of colistin were very low, relative to plasma colistin concentrations, suggesting that colistin permeability across the healthy blood-brain barrier is negligible during this experimental period.Colistin (also known as polymyxin E) is a cationic polypeptide antibiotic and is bactericidal against multidrug-resistant gram-negative pathogens (8). Like other members of the polymyxin family, colistin consists of two major components (colistins A and B), with colistins A and B differing only in the fatty acid side chain. In studies conducted several decades ago, colistin was shown to result in adverse effects after intramuscular or intravenous administration to patients (6, 14); nephrotoxicity and neurotoxicity were the most commonly observed adverse effects. It is possible that the prevalence of such toxicity may have been exaggerated due to a lack of understanding of colistin pharmacology and the use of inappropriate doses (22). Over the last few years, however, resistance to many other antibiotics and limited development of new antibiotics have resulted in an increasing use of colistin, administered in the form of its inactive prodrug, colistin methanesulfonate (CMS) (1), for the treatment of infections caused by gram-negative pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii (5). With its increased use, interest in the pharmacology of this old antibiotic has been rekindled and optimization of dosage regimens is therefore urgently required in order to maximize its efficacy while minimizing potential toxicity.Gram-negative bacterial species are increasingly reported to cause severe central nervous system (CNS) infections, such as meningitis (11,24,26) and ventriculitis (7, 30), which have a high mortality rate if untreated or treated inappropriately. There have been several clinical case reports of successful treatment of meningitis and ventriculitis by parenteral administration of CMS, either alone or in combination with other antibacterials (11,12,18), resulting in eradication of the gramnegative pathogens from the cerebrospinal fluid (CSF). These studies suggest that CMS, or colistin that is generated from CMS in vivo, has the potential to permeate the blood...

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Blood–brain barrier permeability considerations for CNS-targeted compound library design

Cited by 89 publications

References 32 publications

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

Brain Penetration of Colistin in Mice Assessed by a Novel High-Performance Liquid Chromatographic Technique

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