Drug transport across the blood-brain barrier

Bree, J. B. M. M. Van; Boer, Albertus G. de; Danhof, Meindert; Breimer, D. D.

doi:10.1007/bf01977618

Cited by 22 publications

(4 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To accurately determine if a compound has permeated the BBB using brain homogenate studies, it is common to account for the concentration of compound remaining within the brain microvasculature (33). Our group has determined the brain microvascular volume in Swiss Outbred mice to be 0.026 ml/g, using […”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…However, it is unlikely that transport mechanisms are identical between the CNS and peripheral organs due to the specialized environment required for neuronal survival. An additional challenge has been the focus of evaluating drug transporters in endothelial cells, some of which have not been CNS-derived, to the exclusion of pericytes and astroytes 19,20,37 .…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition

Wilkins,

Knerler,

Warshanna

et al. 2024

Preprint

View full text Add to dashboard Cite

SummaryTherapeutically targeting the brain requires interactions with endothelial cells, pericytes, and astrocytes at the blood brain barrier (BBB). We evaluated regional and cell-type specific drug metabolism and transport mechanisms using rhesus macaques andin vitrotreatment of primary human cells. Here, we report heterogenous distribution of representative drugs, tenofovir (TFV), emtricitabine (FTC), and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rivaled hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity, rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition.

show abstract

“…They are used as screening tests in the drug discovery process [13] to study the broad-spectrum of biological activity, including the ability to cross specific biological barriers. The BBB is a selective barrier with the endothelium forming a much tighter interface than peripheral endothelia because the gaps between the capillary endothelial cells in most part of the brain are sealed by tight junctions and thus have a severely limited permeability [14]. The experimental determination of BBB permeability based on in vivo studies requires complex techniques which are usually time consuming and expensive [13,15].…”

Section: Introductionmentioning

confidence: 99%

Molecular and Pharmacokinetic Aspects of Acetylcholinesterase Inhibitory Potential of the Oleanane-type Triterpenes and Their Glycosides

Stępnik,

Kukula-Koch,

Płaziński

2023

Preprint

View full text Add to dashboard Cite

The acetylcholinesterase-inhibitory potential of the oleanane-type triterpenes and their glycosides from the Terminalia arjuna (Combreatceae) bark, i.e. arjunic acid, arjunolic acid, arjungenin, arjunglucoside I, sericic acid, and arjunetin, is presented. The studies are based on the in silico pharmacokinetic and biomimetic studies, the acetylcholinesterase (AChE) inhibitory activity tests, and the molecular docking research. Based on the calculated pharmacokinetic parameters, arjunetin and arjunglucoside I are indicated as able to cross the blood-brain barrier. The compounds of interest exhibit marked acetylcholinesterase inhibitory potential, which was tested in the TLC bioautography test. The longest time to reach brain equilibrium is observed for both the arjunic and arjunolic acids and the shortest one for arjunetin. All compounds exhibit high and relatively similar magnitude of binding energies, varying from ca. -15 to -13 kcal/mol. The superposition of the most favorable positions of all ligands interacting with AChE is analyzed. The correlation between the experimentally determined IC50 values and the steric parameters of the molecules is investigated. The inhibition of the enzyme by the analyzed compounds shows their potential to be used as cognition enhancing agents. For the most potent compound (arjunglucoside I; ARG), the kinetics of AChE inhibition is tested. The Michaelis–Menten constant (Km) for the hydrolysis of the acetylthiocholine iodide substrate was calculated to be 0.011 mM.

show abstract

Drug transport across the blood-brain barrier

Cited by 22 publications

References 39 publications

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

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

Drug Metabolism and Transport Capacity of Endothelial Cells, Pericytes, and Astrocytes: Implications for CNS Drug Disposition

Molecular and Pharmacokinetic Aspects of Acetylcholinesterase Inhibitory Potential of the Oleanane-type Triterpenes and Their Glycosides

Contact Info

Product

Resources

About