Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates

Radan, Milica; Djikić, Teodora; Obradović, Darija; Nikolić, Katarina

doi:10.1016/j.ejps.2021.106056

Cited by 24 publications

(20 citation statements)

References 61 publications

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“…25 In addition, in vitro membranes or other chemical methods are used to study (passive) permeability, like the PAMPA-BBB method, that is extensively used. 26 Although all the above-mentioned techniques have been applied to small molecules, understanding of BBB transport and intrabrain distribution of large molecules is currently a challenge, and huge efforts are being made to further understand the BBB transport mechanisms associated with large molecules' mainly receptor mediated transport. 6…”

Section: In Vitro Methodsmentioning

confidence: 99%

“…These models are rather complicated and time‐consuming and are likely less suitable for high‐throughput studies 25 . In addition, in vitro membranes or other chemical methods are used to study (passive) permeability, like the PAMPA‐BBB method, that is extensively used 26 …”

Section: Assessment Of Bbb Transport and Intra‐brain Distributionmentioning

confidence: 99%

“… 25 In addition, in vitro membranes or other chemical methods are used to study (passive) permeability, like the PAMPA‐BBB method, that is extensively used. 26 …”

Section: Assessment Of Bbb Transport and Intra‐brain Distributionmentioning

confidence: 99%

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Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Lange

Udenaes

2022

Clin Pharma and Therapeutics

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This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood‐brain barrier (BBB) transport and intra‐CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle‐based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.

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Section: In Vitro Methodsmentioning

confidence: 99%

Section: Assessment Of Bbb Transport and Intra‐brain Distributionmentioning

confidence: 99%

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Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Lange

Udenaes

2022

Clin Pharma and Therapeutics

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“…ROP-HCl possesses relatively low permeability toward BBB. 14 There has been lot of work done on ROP-HCl so far with Ethosomal formulations, Hydrogel based nanoparticles, polymer-lipid nanoparticles and chitosan coated Nanoparticles for controlled release and intranasal delivery. [15][16][17][18][19][20] The details are summarized in Table 2.…”

Section: Introductionmentioning

confidence: 99%

Statistically Optimized Facile Development, Characterization and Evaluation of Niosomal Nasal Drug Delivery System of Ropinirole Hydrochloride: In vitro Drug Release, Cytotoxicity and ex vivo Permeability Studies

Suryanarayana¹,

Vinukonda²,

Saroj³

et al. 2023

Ind. J. Pharm. Edu. Res

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Introduction: Nasal route is an alluring route for direct drug delivery to the central nervous system (CNS), owing to its avoidance of the hepatic first-pass metabolism and deciphering the blood-brain barrier passage issues. ROP-HCl has a lower experimental BBB permeability therefore ROP-HCl freighted niosomes were fabricated by ethanol injection method and served two purposes one being a novel Niosomal formulation impacting the permeability and other obtaining a sustained release property which likely would lead to an improved bioavailability of ROP-HCl. Objectives: The present study is aimed to develop a stable non-ionic surfactant vesicle; Niosomes embodying Ropinarole Hydrochloride (ROP-HCl) for ameliorated treatment of Parkinson's disease (PD) by statistical optimization employing a 3-level factorial design using Design Expert® software. Materials and Methods: All the formulations were characterized physiochemically and morphologically. Additionally, the drug and excipients interaction studies were evaluated using Differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR). Further, in vitro release kinetics using DD solver excel add-in and mechanism was studied for developed Niosomal formulation. Cytotoxicity study was studied in Raw 264.7 cells. in a concentration dependent manner and ex vivo, permeability was done using sheep mucosa. Toxicity was studied by histological examination. Results: The IC 50 value of developed Niosomes was lower than drug itself and further the permeability of developed Niosomes was considerably enhanced compared to ROP-HCl alone. Histological examination revealed safe nature of developed formulation. Conclusion: These results conveyed that, Niosomes can be a valuable carrier for the nasal delivery of ROP-HCl to CNS.

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“…The ability to create a direct link between moieties, molecular descriptors, and biological activity should be an integral part of the research [ 19 , 20 ]. Unfortunately, the H-GETAWAY interpretation usually contains some shortcomings [ 21 , 22 , 23 , 24 , 25 ]. The problem lies in interpreting H-GETAWAY descriptors based mainly on leverages, which are not computed but estimated from a visual assessment of the molecular shape.…”

Section: Introductionmentioning

confidence: 99%

HATS5m as an Example of GETAWAY Molecular Descriptor in Assessing the Similarity/Diversity of the Structural Features of 4-Thiazolidinone

Zapadka

Dekowski²,

Kupcewicz

2022

IJMS

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Among the various methods for drug design, the approach using molecular descriptors for quantitative structure–activity relationships (QSAR) bears promise for the prediction of innovative molecular structures with bespoke pharmacological activity. Despite the growing number of successful potential applications, the QSAR models often remain hard to interpret. The difficulty arises from the use of advanced chemometric or machine learning methods on the one hand, and the complexity of molecular descriptors on the other hand. Thus, there is a need to interpret molecular descriptors for identifying the features of molecules crucial for desirable activity. For example, the development of structure–activity modeling of different molecule endpoints confirmed the usefulness of H-GETAWAY (H-GEometry, Topology, and Atom-Weights AssemblY) descriptors in molecular sciences. However, compared with other 3D molecular descriptors, H-GETAWAY interpretation is much more complicated. The present study provides insights into the interpretation of the HATS5m descriptor (H-GETAWAY) concerning the molecular structures of the 4-thiazolidinone derivatives with antitrypanosomal activity. According to the published study, an increase in antitrypanosomal activity is associated with both a decrease and an increase in HATS5m (leverage-weighted autocorrelation with lag 5, weighted by atomic masses) values. The substructure-based method explored how the changes in molecular features affect the HATS5m value. Based on this approach, we proposed substituents that translate into low and high HATS5m. The detailed interpretation of H-GETAWAY descriptors requires the consideration of three elements: weighting scheme, leverages, and the Dirac delta function. Particular attention should be paid to the impact of chemical compounds’ size and shape and the leverage values of individual atoms.

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Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates

Cited by 24 publications

References 61 publications

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

Statistically Optimized Facile Development, Characterization and Evaluation of Niosomal Nasal Drug Delivery System of Ropinirole Hydrochloride: In vitro Drug Release, Cytotoxicity and ex vivo Permeability Studies

HATS5m as an Example of GETAWAY Molecular Descriptor in Assessing the Similarity/Diversity of the Structural Features of 4-Thiazolidinone

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