An extended substrate spectrum of the proton organic cation antiporter and relation to other cation transporters

Abstract Most central nervous system (CNS) active drugs are organic cations, which need carrier proteins for efficient transfer through the blood–brain barrier (BBB). A genetically still unidentified proton organic cation (H+/OC) antiporter is found in several tissues, including endothelial cells of the BBB. We characterized the substrate spectrum of the H+/OC antiporter and the overlap in substrate spectrum with OCTN1, OCTN2 or OCT3 by screening 87 potential substrates for transport activity. Based on high antiport rates, 45 of the tested substances were substrates of the H+/OC antiporter. They included antidepressants (like tranylcypromine or nortriptyline), antipsychotics (like levomepromazine) and local anaesthetics. Concentration‐dependent transport was confirmed for 38 of the substrates. Transport uptake depending on a pH gradient across the cell membrane confirmed that 43 drugs were indeed substrates of the H+/OC antiporter. However, the patterns of pH dependence differed between the substrates, possibly indicating different modes of transport or the existence of multiple antiporter proteins. The substrate overlap between the H+/OC antiporter and OCTN1, OCTN2 or OCT3 was minimal, indicating that the latter three are not the proteins underlying the H+/OC antiporter activity. Overall, about 50% of positively charged drugs may be substrates of the antiporter, which may be the most important membrane transport protein for many drugs.