In silico, in vitro, and in vivo methods to analyse drug permeation across the blood-brain barrier: A critical review

Abstract

IntroductionThe existence of the blood-brain barrier in the human body leads to the insufficiency in delivering therapeutic compounds into the brain for the effective treatment of various neurological disorders. In order to determine the possibility of such agents to penetrate through the blood-brain barrier, different in silico, in vitro and in vivo methods may be implemented. Some of them are often provided with unreliable results while others are not feasible in high-throughput screening environment. The goal of this review was to characterise the latest state-of-the-art methods that have been developed and used in the pharmaceutical research in the last few decades to assess the permeation of novel therapeutic entities across the blood-brain barrier.We carried out a literature research and study selection by searching for published biomedical articles in the PubMed archive. Conclusion Overall, the combination of in silico, in vitro and in vivo methods in the bloodbrain barrier research may lead to the discovery of promising drug compounds and more accurate information of brain uptake mechanisms.

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

“…The evaluation of the compound's ability to cross the BBB is a vital step in assessing its therapeutic potential because many promising neurotherapeutics miss their goal due to their inability to enter the brain or, oppositely, peripherally acting drugs exhibit unwanted side effects due to their undesired brain penetration. The in vivo, in vitro and in silico methods used currently to study the drug brain penetration are discussed in a number of review papers [2,5,6]. High costs and low throughput of any in vivo experiments as well as the need to use lab animals are the reasons why several in vitro cellbased methods of the BBB permeation assessment have been developed [7].…”

“…Concurrently with the development of the in vitro cell-based techniques, some non-cell-based assays have been introduced [8]. As more data on the CNS activity of different compounds were gathered, several attempts were made to generate computational models linking the BBB permeability of compounds to their experimentally measured and/or theoretically calculated physicochemical features [4,5].…”

Building In Silico Models to Trigger Retesting: A Strategy on How to Use Predictive Models to Identify Potentially Incorrect In Vitro Intrinsic Clearance Results

“…Typically, it is assumed that in vitro data are less relevant than in vivo data and that in silico data are even less relevant than in vitro data. [1][2][3][4] Hepatic metabolism, for example, is the major clearance process for the majority of marketed drugs. 5 In vitro systems, such as human hepatocyte and liver microsomal clearance, have proven key for predicting in vivo human metabolic clearance.…”

Blood–brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate

“…2,3 On the other hand, there is a significant misconception that small molecules can easily pass through the BBB, but it has been affirmed that the majority of them do not permeate the BBB. 4,5 Low molecular weight and high lipophilic properties are the factors that contribute to a better drug delivery in the CNS.…”