Update on drug-drug interaction at organic cation transporters: mechanisms, clinical impact, and proposal for advancedin vitrotesting

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Abstract
Introduction: Organic cation transporters collectively called OCTs belong to three gene families (SLC22A1 OCT1, SLC22A2 OCT2, SLC22A3 OCT3, SLC22A4 OCTN1, SLC22A5 OCTN2, SLC29A4 PMAT, SLC47A1 MATE1, and SLC47A1 MATE2-K). OCTs transport structurally diverse drugs with overlapping selectivity. Some OCTs were shown to be critically involved in pharmacokinetics and therapeutic efficacy of cationic drugs. Drug-drug interactions at individual OCTs were shown to result in clinical effects. Procedures for in vitro testing of drugs for interaction with OCT1, OCT2, MATE1, and MATE2-K have been recommended. Areas covered: Considering data on OCTs published within the last seven years, an overview about functional properties, cation selectivity, location, and clinical impact of OCTs is provided. In addition, clinically relevant drug-drug interactions at OCTs are compiled. Because it was observed that the half maximal concentration of drugs to inhibit transport by OCTs (IC50) is dependent on the transported cation and its concentration, an advanced protocol for in vitro testing of drugs for interaction with OCTs is proposed. In addition, it is suggested to include OCT3 and PMAT for in vitro testing. Expert opinion: Research on clinical roles of OCTs should be reinforced including more transporters and drugs. An improvement of the in vitro testing protocol considering recent data is imperative for the benefit of patients.

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