Abstract
One of the main obstacles in neurological disease treatment is the presence of the blood–brain barrier. New predictive high-throughput screening tools are essential to avoid costly failures in the advanced phases of development and to contribute to the 3 Rs policy. The objective of this work was to jointly develop a new in vitro system coupled with a physiological-based pharmacokinetic (PBPK) model able to predict brain concentration levels of different drugs in rats. Data from in vitro tests with three different cells lines (MDCK, MDCK-MDR1 and hCMEC/D3) were used together with PK parameters and three scaling factors for adjusting the model predictions to the brain and plasma profiles of six model drugs. Later, preliminary quantitative structure–property relationships (QSPRs) were constructed between the scaling factors and the lipophilicity of drugs. The predictability of the model was evaluated by internal validation. It was concluded that the PBPK model, incorporating the barrier resistance to transport, the disposition within the brain and the drug–brain binding combined with MDCK data, provided the best predictions for passive diffusion and carrier-mediated transported drugs, while in the other cell lines, active transport influence can bias predictions.
Highlights
The brain is the most important organ in living beings as it controls their vital functions: nutrition, interaction and reproduction
Besides the physicochemical protection of the blood–brain barrier (BBB), the brain is protected by the cerebrospinal fluid (CSF), a constantly secreted liquid that helps to maintain the brain’s homeostasis for normal neurological function, acts as a cushion between the brain and the skull, and makes the central nervous system (CNS) apparently “lighter”, as it is floating in this liquid [1]
Dulbecco’s modified eagle’s medium (DMEM) with a high content of glucose, Lglutamine, HEPES, MEM non-Essential aminoacid, penicillin−streptomycin, trypsinEDTA, Hank’s balanced salt solution (HBSS) and fetal bovine serum (FBS) for the cell culture of MDCK and MDCK-MDR1 cell lines were purchased from Sigma-Aldrich (Barcelona, Spain)
Summary
The brain is the most important organ in living beings as it controls their vital functions: nutrition, interaction and reproduction. The importance of the brain means all the capillaries that supply it with oxygen and nutrients are composed of extremely tight endothelial cells surrounded by a thick layer of astrocytes and pericytes, all of this to prevent dangerous substances from reaching it. This group of protective and regulating cells is known as the blood–brain barrier (BBB). Besides the physicochemical protection of the BBB, the brain is protected by the cerebrospinal fluid (CSF), a constantly secreted liquid that helps to maintain the brain’s homeostasis for normal neurological function, acts as a cushion between the brain and the skull, and makes the central nervous system (CNS) apparently “lighter”, as it is floating in this liquid [1]. The pharmaceutical industry has developed several strategies to bypass the BBB: chemical strategies, such as the development of prodrugs or chemical drug delivery systems (CDDS), physical strategies, such as the use of ultrasounds to tem-
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