The role of multidrug resistance protein (MRP-1) as an active efflux transporter on blood–brain barrier (BBB) permeability

Abstract

Drugs acting on central nervous system (CNS) may take longer duration to reach the market as these compounds have a higher attrition rate in clinical trials due to the complexity of the brain, side effects, and poor blood-brain barrier (BBB) permeability compared to non-CNS-acting compounds. The roles of active efflux transporters with BBB are still unclear. The aim of the present work was to develop a predictive model for BBB permeability that includes the MRP-1 transporter, which is considered as an active efflux transporter. A support vector machine model was developed for the classification of MRP-1 substrates and non-substrates, which was validated with an external data set and Y-randomization method. An artificial neural network model has been developed to evaluate the role of MRP-1 on BBB permeation. A total of nine descriptors were selected, which included molecular weight, topological polar surface area, ClogP, number of hydrogen bond donors, number of hydrogen bond acceptors, number of rotatable bonds, P-gp, BCRP, and MRP-1 substrate probabilities for model development. We identified 5 molecules that fulfilled all criteria required for passive permeation of BBB, but they all have a low logBB value, which suggested that the molecules were effluxed by the MRP-1 transporter.

Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine

“…P-gp and BCRP are the examples of efflux pumps which have broad substrate specificity and are able to actively transport substrates back into systemic circulation (80). In addition to P-gp and BCRP, multidrug resistance-associate proteins (MRPs) can also be involved in actively limiting the brain delivery of certain drugs (90,91). In the treatment of brain tumors, the BBB often limits the brain distribution of therapeutic agents through the efflux activity of ATP binding cassette (ABC) transport proteins (70,80,92–100).…”

Modeling blood–brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms

“…These are very important determinants of drug uptake into brain. Examples of this group of transporters are P-glycoprotein (P-gp/MDR1; ABCB1), breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated proteins (MRP; ABCC) 1, 4, 5, and 6 [78][79][80][81][82] (Fig. 2b).…”

Cell Migration Related to MDR—Another Impediment to Effective Chemotherapy?

“…One of the most important functions of ABC proteins as efflux pumps is the creation of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB), which maintain brain homeostasis by eliminating metabolic waste products and preventing the uptake of both endogenous and exogenous potentially harmful substances [ 105 , 106 , 107 ]. The BBB is composed of a monolayer of brain microvessel endothelial cells joined by tight junctions to create an impermeable barrier surrounded by pericytes, astrocytes, and neurons.…”