The mystery of the human proton-organic cation antiporter: One transport protein or many?

About 30% of all small molecular drugs are organic cations (OCs). If these are more or less hydrophilic, they require membrane transporters to pass through biological membranes. Here, the proton-organic cation (H OC) antiporter may play a physiologically most relevant role, particularly concerning passage through the blood-brain barrier. Membrane transport of about 70 OCs is significantly enhanced by this H OC antiporter. Surprisingly still today the gene coding for this antiporter was not yet identified. However, the H OC antiporter is characterized by concentration- and pH-dependent uptake, antiport with another OC, and susceptibility to inhibition by specific inhibitors. Moreover, in the studied tissues and cell types, transport is not mediated by already well-known organic cation transporters. The review explains the typically used assays to identify potential substrates of the H OC antiporter. Thus far, the gene encoding for this transporter has not yet been identified, but a better understanding of this protein may be most relevant because it may affect the pharmacokinetics of up to 10% of all low molecular substances. This review summarizes the known functional characteristics of the H OC antiporter, its cell and tissue expression, and its substrate spectrum. Summarizing the features of the substrates of the H OC antiporter may even suggest that for OCs, good penetration through the blood-brain barrier is almost synonymous with being a substrate of the H OC antiporter. In clinical studies, pharmacokinetics of typical substrates of the antiporter showed outstanding between-subject variability.