Renal drug transporters and their significance in drug-drug interactions

Abstract

The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug-drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.

Keywords: ABC, ATP-binding cassette; ATP, adenosine triphosphate; AUC, area under the plasma concentration curve; BBB, blood–brain barrier; CHO, Chinese hamster ovary; CL, plasma clearance; CLR, renal clearance; Cmax, maximum plasma concentration; DDIs, drug–drug interactions; Drug–drug interactions; FDA, U.S. Food and Drug Administration; GSH, glutathione; HEK, human embryonic kidney; IC50, half maximal inhibitory concentration; ITC, International Transporter Consortium; Ki, inhibitory constant; MATE, multidrug and toxin extrusion protein; MPP+, 1-methyl-4-phenylpyridimium; MRP, multidrug resistance-associated protein; MSD, membrane-spanning domain; MW, molecular weight; NBD, nucleotide-binding domain; NME, new molecular entity; NSAID, non-steroidal anti-inflammatory drugs; Nephrotoxicity; OA, organic anion; OAT or Oat, organic anion transporters; OATP or Oatp, organic anion-transporting peptide; OC, organic cation; OCT or Oct, organic cation transporter; OCTN, Organic zwitterions/cation transporters; Organic anions; Organic cations; P-gp, P-glycoprotein; PAH, p-aminohippurate; Renal drug transporters; SLC, solute carrier; SNP, single-nucleotide polymorphism; TEA, tetraethylammonium; TMD, transmembrane domain; URAT, urate transporter; fe, fraction of the absorbed dose excreted unchanged in urine.

Figure 1

Major drug transporters expressed in human renal proximal tubule cells. ADP, adenosine diphosphate; ATP, adenosine triphosphate; DC, dicarboxylate; OA, organic anion; and OC, organic cation.

Figure 2

Hypothesized effects of transporter inhibition on tubular drug secretion and intracellular accumulation. When a basolateral uptake transporter such as hOCT2 is the main inhibition site, both renal secretion and intracellular drug accumulation are decreased. In contrast, when an apical efflux transporter such as hMATE1 is the primary inhibition site, tubular secretion is decreased but the intracellular drug level is increased.