Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

Abstract

Most drugs are intended to act on molecular targets residing within a specific tissue or cell type. Therefore, the drug concentration within the target tissue or cells is most relevant to its pharmacological effect. Increasing evidences suggest that drug transporters not only play a significant role in governing systemic drug levels, but are also an important gate keeper for intra-tissue and intracellular drug concentrations. This review focuses on polyspecific organic cation transporters, which include the organic cation transporters 1-3 (OCT1-3), the multidrug and toxin extrusion proteins 1-2 (MATE1-2) and the plasma membrane monoamine transporter (PMAT). Following an overview of the tissue distribution, transport mechanisms, and functional characteristics of these transporters, we highlight the studies demonstrating the ability of locally expressed OCTs to impact intracellular drug concentrations and directly influence their pharmacological and toxicological activities. Specifically, OCT1-mediated metformin access to its site of action in the liver is impacted by genetic polymorphisms and chemical inhibition of OCT1. The impact of renal OCT2 and MATE1/2-K in cisplatin intrarenal accumulation and nephrotoxicity is reviewed. New data demonstrating the role of OCT3 in salivary drug accumulation and secretion is discussed. Whenever possible, the pharmacodynamic response and toxicological effects is presented and discussed in light of intra-tissue and intracellular drug exposure. Current challenges, knowledge gaps, and future research directions are discussed. Understanding the impact of transporters on intra-tissue and intracellular drug concentrations has important implications for rational-based optimization of drug efficacy and safety.

Keywords: Drug transporter; Intracellular drug concentration; MATE; OCT; PMAT; Pharmacodynamics.

Figure 1

Models of organic cation transport in liver hepatocytes (A) and kidney proximal tubule cells (B).

Figure 2

(A) A proposed model of OCT3-mediated metformin transport in salivary gland epithelial cells. OCT3 on the basolateral membrane of epithelial cells mediates metformin uptake from the blood into the cells. Once metformin is highly concentrated inside the cells, OCT3 on the apical membrane can facilitate efflux of metformin into the saliva. (B) Impact of Oct3 on metformin exposure, defined as area under the concentration-time curve (AUC), in plasma, salivary glands and kidney. Data were compiled from [43].