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.

Introduction

The ability of a drug molecule to move through cell membranes is a vital property affecting its pharmacokinetic and pharmacodynamic properties. Lipophilic drugs generally have high membrane permeability and their movement across cell membranes occurs primarily through passive diffusion, a non-mediated process discussed in great details elsewhere in this issue. Hydrophilic drugs, on the other hand, have low membrane permeability, and their efficient uptake into cells and tissues often involve facilitated mechanisms mediated by membrane transporters (also known as carriers). Different from passive diffusion where a drug molecule moves across membranes down its concentration gradient without energy input, carrier-mediated transport can be coupled to a cellular energy source to power uphill transport against the drug concentration gradient. Further, carrier-mediated drug transport is saturable, inhibitable, and highly dependent on the functional characteristics of the membrane transporters expressed in the specific tissues or cell types. In mammalian cells, there are two major types of membrane proteins involved in drug and solute transport: the solute carrier (SLC) and the ATP-binding cassette (ABC) transporters. The past two decades have witnessed an explosion of knowledge in our understandings of the basic biology and pharmacology of various SLC and ABC drug transporters. The in vivo roles of these transporters in drug disposition, efficacy, and toxicity are increasingly being appreciated. The clinical significance of transporters as a site of drug⿿drug interaction and a source for interindividual variability in drug response is also begining to be acknowledged [1], [2], [3].

Most drugs are intended to act on targets residing within a specific tissue or cells. While some drugs bind to external cell surface targets (e.g. G protein-coupled receptors), others act on intracellular enzymes and receptors residing inside the cell. Thus, it is the unbound drug concentration within the target tissue or cells that is directly responsible for eliciting its pharmacological effect. However, in the clinical setting, direct measurement of drug concentrations in target tissues and cells is difficult to achieve. Measurement of blood or plasma drug concentrations is thus commonly used to establish pharmacokinetic⿿pharmacodynamic relationships. For drugs that rapidly cross membranes by passive diffusion, plasma concentration is often a good surrogate for tissue concentration because the unbound drug concentration in tissue/cells is at equilibrium with its unbound concentration in plasma at steady state [4], [5]. However, if a drug is transported by active uptake and/or efflux drug transporters, such a relationship may no longer exist. For drugs that are substrates of uptake transporters, tissue and/or intracellular drug concentrations can be much higher than drug concentrations in plasma. Conversely, for drugs that are substrates of efflux transporters, concentrations in tissues and cells may be substantially lower than predicted from plasma levels. Increasing evidences suggest that transporters expressed in specific tissues and cells can exert a great impact on local and intracellular drug concentrations, directly influencing their pharmacological and toxicological activities [4], [5].

This review focuses on a special group of SLC drug transporters⿿the polyspecific organic cation transporters, which mediate cellular uptake and efflux of a broad spectrum of drugs, toxins, and endogenous compounds. We first briefly review the molecular and functional characteristics of major organic cation transporters with a special emphasis on their tissue distribution, cellular localization and transport mechanisms. We then highlight the impact of these transporters in controlling tissue and intracellular drug concentrations using literature examples where the roles of locally expressed organic cation transporters have been clearly demonstrated in several tissues (liver, kidney, salivary glands) in in vivo or clinical studies. The resulting consequence on pharmacodynamic response and toxicological effects of clinically used organic cation drugs is presented and discussed alongside. Lastly, the current challenges, knowledge gaps and future research directions in this field are briefly summarized and discussed.