Blood-brain barriers and drug pharmacokinetics: mechanisms and models

Development of new drugs for the effective treatment of brain diseases is one of the most important challenges in modern neuropharmacology. In vivo testing of pharmacokinetic and pharmacodynamic parameters is a long-lasting process, whereas simplified in vitro models do not fully reflect the complexity of drugs distribution in the tissue. There is a growing interest in the establishment of new in vitro models reproducing the complex spatial tissue architecture, brain tissue compartmentalization and continuous circulation of fluids (blood plasma, interstitial fluid, and cerebrospinal fluid). Microfluidic technologies are becoming increasingly popular for in vitro modeling the brain barriers (blood-brain barrier, blood-cerebrospinal fluid barrier, etc.) and brain tissue modules. Application of such models allows controlling the transfer of compounds into the brain parenchyma, their local metabolism, elimination, and pharmacological activity. Each type of modeling (either in vivo or in vitro) is designed to fulfil a specific set of tasks and is oriented towards a particular field of applications. Recently, digital twins of in vivo and in vitro models have been proposed for the in silico analysis in Neuropharmacology. In this review, we focus on current achievements, limitations and prospects in the assessment of pharmacokinetics of neuropharmaceuticals in physiologically relevant brain tissue in vitro models.