Methodologies to Assess Drug Permeation Through the Blood–Brain Barrier for Pharmaceutical Research

Abstract

The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier.

Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis

“…BBB permeability and P-gp-mediated efflux assays. To compare the permeability of diamidines across the BBB, the MDR1-transfected MDCK (MDR1-MDCK) cell monolayer model was chosen as an in vitro BBB model due to its simplicity and its similar predictability when compared to other existing in vitro models that use cells derived from brain endothelium (14)(15)(16). The bidirectional permeabilities, apical-to-basolateral (A-B) and basolateral-to-apical (B-A), of diamidines across the wild-type (WT) MDCK and MDR1-MDCK cell monolayers were determined as described previously (17).…”

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

“…For example, transport of nanoparticles into the brain in vivo is a combined outcome of immune clearance and permeation across the BBB, thus making it difficult to deconvolute the contributions of each factor from the measured experimental outcome. Common techniques to investigate BBB transport of therapeutics in vivo include single carotid injections, internal carotid artery perfusion, and intravenous injections . Using intravenous injections can be disadvantageous for investigating BBB transport due to the potential rapid metabolism of the therapeutic, resulting in metabolism‐induced artifacts and greater likelihood of clearance before reaching the brain microcirculation.…”

“…Common techniques to investigate BBB transport of therapeutics in vivo include single carotid injections, internal carotid artery perfusion, and intravenous injections. 11,12 Using intravenous injections can be disadvantageous for investigating BBB transport due to the potential rapid metabolism of the therapeutic, resulting in metabolism-induced artifacts and greater likelihood of clearance before reaching the brain microcirculation. Alternatively, single carotid injections and internal carotid artery perfusions can reduce the likelihood of clearance while also limiting metabolic events within the brain microcirculation.…”

“…LIVE/DEAD™ Cell Vitality Assay Kit, C12 Resazurin/SYTOX™ Green was used to assess cell viability under static culture, after conditioning to flow, and after dextran transport. Briefly, 10 nM of Sytox green and 500 nM of C 12 -resazurin was injected in the device.…”

Application Of Nanotechnology In Agriculture And Food Industry, Its Prospects And Risks

“…Generally strategies/structural modifications to improve permeability are based on a few fundamental concepts: reduction of ionizability, increase of lipophilicity, reduction of polarity or reduction of hydrogen bond donors or acceptors [1][2][3][4]. Formulations [77][78][79][80][81][82][83][84][85]. Some papers disclosing examples of using the properties of controlled-release formulations contributed to the development of the CRF in the agricultural field [86,87].…”