Mechanisms of renal anionic drug transport

Abstract

By utilizing filtration, active secretion and reabsorption processes, the kidney can conserve essential nutrients, and eliminate drugs and potentially toxic compounds. Active uptake of organic anions and cations across the basolateral membrane, and their extrusion into the urine across the brush border membrane mainly takes place in the renal proximal tubule cells, and is facilitated via a range of substrate-specific tubular transporters. Many drugs and their phase II conjugates are anionic compounds, and therefore renal organic anion transporters are important determinants of their distribution and elimination. Competition for renal excretory transporters may cause drugs to accumulate in the body leading to toxicity, which is a potential hazard of concomitant drug administration. Here, we present a brief update on the most prominent human proximal tubule organic anion transporters, which either belong to the ATP-binding cassette (ABC) or the solute carrier transporter (SLC) families. We focus on the participation of the individual transporters in renal anionic drug elimination, in an attempt to understand their overall biological and pharmacological significance, hoping to inspire further studies in the renal transporters field.

Introduction

The kidney plays a critical role in conserving essential nutrients and eliminating natural end products, toxins, drugs and drug metabolites. It consists of approximately 1 million functional units, which are called nephrons. The sum of the processes of glomerular filtration, active tubular secretion and reabsorption that a compound can undergo in each of the nephrons, determines its net renal excretion rate. Active drug secretion and reabsorption mainly take place in the proximal tubule cells, which are equipped with separate transport systems for organic anions and cations, each consisting of multiple transporters localised in the plasma membrane at both sides of the cell and with overlapping substrate specificities. Both systems are characterised by a high clearance capacity and broad diversity of substances accepted.

This review is devoted to the transporters that drive renal organic anion excretion. Recent research has provided much insight into their molecular characteristics. Because the renal organic anion transport system also accepts many phase II metabolites in addition to unconjugated anionic compounds, they play a critical role in the elimination of a large number of xenobiotics. The renal organic cation transporters have been recently reviewed by others (Koepsell et al., 2007) (Terada and Inui, 2007). Several groups of organic anion transporters in the proximal tubule cell mediate the uptake of compounds from blood across the basolateral membrane (BLM), followed by their secretion into the urine through the brush border membrane (BBM, also known as apical or luminal membrane) (Fig. 1). It has been suggested that the rate-limiting step for excretion of organic anions is the uptake step at the BLM, although their concentration inside the proximal tubule cells is higher than outside, either at the BLM or BBM side (Wright and Dantzler, 2004). This suggests that net transport across both membranes facilitates the intracellular accumulation of organic anions, and that the BBM controls the final exit into the urine via ATP-powered transporters and bidirectional exchangers. Furthermore, reabsorption processes may also contribute to intracellular organic anion accumulation, which in turn can affect BLM gradient-sensitive processes.

Several methods have been employed to study carrier-mediated organic anion transport. The recent use of knockout animals provides a powerful tool, yet one that is not devoid of limitations. In addition to possible up- or down-regulation of compensatory transporters and the possible inter-species variations (Johnson et al., 2006) (Chu et al., 2006), other feedback mechanisms, as for example the saturation of metabolic pathways, can restrain the use of such models. Investigations using the isolated perfused kidney from transporter deficient animals (Masereeuw et al., 2003) aimed at circumventing some of these factors. Yet, the actual transport across the cell membrane may be the most solid proof to characterize a compound as a substrate of a certain transporter protein. With the recent advances in molecular cloning methodologies, several cellular models have evolved that are transfected to over-express one or more transporters, including Xenopus laevis oocytes, Spodoptera frugiperda insect (Sf9) cells, and mammalian cell lines of animal and human origin (Masereeuw and Russel, 2004). These different cell types have been used for transport studies in the form of cellular monolayers, transwell transport studies or transport in isolated inside-out membrane vesicles. Ultimately, combining the results of diverse molecular, cellular and in vivo studies are required to identify the role of individual transporters in the overall renal handling of drugs. In this review, we present an updated overview of the major human organic anion transporter proteins involved in renal proximal tubular drug handling, focusing on members of the ATP-binding cassette (ABC) C and solute carrier (SLC) 22A subfamilies.