Restricting CNS penetration of drugs to minimise adverse events: role of drug transporters

Some drug discovery approaches can benefit from restricting the access of compounds to the central nervous system (CNS) to minimise the risk of side-effects. Designing compounds that act as substrates for efflux transporters in the blood–brain barrier can achieve CNS restriction without significantly impairing absorption in the intestine. In vitro assays can be deployed to optimise a balance between passive permeability and active efflux via the ABC family transporters P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) whilst in vivo estimates of distribution of unbound concentrations of drug are needed to understand pharmacologically relevant exposure in peripheral and central compartments. This strategy can deliver significant CNS restriction whilst retaining good oral bioavailability, cell penetration and pharmacological activity. The possible risks of targeting P-gp and BCRP in orally delivered drugs are discussed.