Organic cation transporters 2: Structure, regulation, functions, and clinical implications

The SLC22A2 gene encodes organic cation transporter 2 (OCT2), which is predominantly expressed in renal proximal tubule cells. OCT2 is critical for the active renal excretion of various cationic drugs and endogenous metabolites. OCT2 expression varies across species, with higher levels in mice and monkeys compared with humans and rats. The human OCT2 protein consists of 555 amino acids and contains 12 transmembrane domains. OCT2 functions as a uniporter, facilitating the bidirectional transport of organic cations into renal tubular cells, driven by the inside-negative membrane potential. Its expression is regulated by sex hormones, contributing to potential sex differences in Oct2 activity in rodents. OCT2 has been linked to tissue toxicity, such as cisplatin-induced nephrotoxicity. Factors such as genetic variants, age, disease states, and the coadministration of drugs, including tyrosine kinase inhibitors, contribute to interindividual variability in OCT2 activity. This, in turn, impacts the systemic exposure and elimination of drugs and endogenous substances. Regulatory agencies recommend evaluating the potential of a drug to inhibit OCT2 through in vitro and clinical drug-drug interaction (DDI) studies, often using metformin as a probe substrate. Emerging tools like transporter biomarkers and physiologically based pharmacokinetic modeling hold promise in predicting OCT2-mediated DDIs. While several OCT2 biomarkers, such as N1-methylnicotinamide, have been proposed, their reliability in predicting renal DDIs remains uncertain and requires further study. Ultimately, a better understanding of the factors influencing OCT2 activity is essential for achieving precision medicine and minimizing renal and systemic toxicity. SIGNIFICANCE STATEMENT: Organic cation transporter 2 (OCT2) is essential for the active tubular secretion of xenobiotics and endogenous cationic substances in the kidneys. This article offers a comprehensive overview of the tissue distribution, interspecies differences, and factors affecting its activity-critical for evaluating tissue toxicity and systemic exposure to cationic substances. Using OCT2 biomarkers and integrating OCT2 activity and expression data into physiologically based pharmacokinetic models are valuable tools for predicting OCT2 function and its clinical implications.