Successful neuropharmacology requires optimization of CNS drug delivery and, subsequently, free drug concentrations at brain molecular targets. As such, a rigorous assessment of blood-brain barrier (BBB) and neurovascular unit (NVU) physiological characteristics is necessary to achieve this goal. This knowledge will permit the innate biology of the BBB/NVU to be leveraged for improved bench-to-bedside translation of neurotherapeutics. The "next frontier" in CNS drug delivery is targeting BBB uptake transporters, an approach that requires evaluation of brain endothelial transport mechanisms so that effective drug accumulation and improved therapeutic efficacy can occur. Indeed, BBB permeability of drugs is governed by tight junction protein complexes (i.e., physical barrier) and transporters/enzymes (i.e., biochemical barrier). For most drugs, a component of blood-to-brain transport involves passive transcellular diffusion. Small molecule therapeutics that do not possess acceptable physicochemical characteristics for passive permeability can utilize membrane transporters for CNS uptake. While both uptake (e.g.: SLC transporters such as organic anion transporting polypeptides (Oatps) and organic cation transporters (Octs)) and efflux (e.g.:, ATP-binding cassette transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (Bcrp)) are expressed at the brain microvascular endothelium, uptake transporters can be targeted for optimization of brain drug delivery and improved drug targeting for treatment of neurological disease states. This symposium presentation will present state-of-the-art knowledge on BBB uptake transporters for small molecule therapeutics and emphasize how the endogenous biology of the BBB can be leveraged for improved CNS drug delivery. Additionally, this presentation will demonstrate how a rigorous understanding of these transporters is required to improve translation from the bench to the bedside and to stimulate development of new treatment paradigms for neurological disease states.
Learning Objectives:
Upon completion, participants will be able to describe how the tight junction protein complexes and transporters contribute to the physical and biochemical characteristics of the blood-brain barrier (BBB).
Upon completion, participants will be able to discuss utility of critical BBB uptake transporters (i.e, organic anion transporting polypeptides (Oatps), organic cation transporters (Octs)) in therapeutic targeting to the brain.
Upon completion, participants will be able to describe how endogenous drug delivery mechanisms at the BBB can be leveraged for improved therapeutic efficacy of neurotherapeutics.
