Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Abstract

The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

Keywords: ATP-Binding Cassette Transporters; Acute Kidney Injury; Anti-Bacterial Agents; Cations; Chronic; Diuretics; Organic Anion Transporters; Renal Insufficiency; drug transporter; nephrotoxicity; renal physiology.

Figure 1.

Transcellular movement of organic cations (OCs) and organic anions (OAs) in kidney proximal tubule epithelial cells. (A) Transcellular movement of OCs in a kidney proximal tubule epithelial cell. Movement of OCs are facilitated by the negative potential difference within the cell, which is maintained by the basolateral Na⁺,K⁺-ATPase (not shown). OCs enter the cell across the basolateral membrane by organic cation transporters (OCTs), such as OCT2. The authors note that OCT2 is also sometimes depicted as an OC exchanger. Secretion across the apical membrane into the lumen occurs by electroneutral exchange with H⁺ by solute carrier (SLC) transporters, including multidrug and toxin extrusion (MATE) protein 2/2K, and by ATP-binding cassette (ABC) transporters, such as multidrug-resistant protein 1 (MDR1), which use energy generated by ATP hydrolysis to transport molecules across the apical membrane. Only a fraction of the known transporters are shown. (B) OA transport via organic anion transporters (OATs) in a proximal tubule epithelial cell. Primary active transport of sodium out of the cell by the basolateral Na⁺,K⁺-ATPase creates the gradient that facilitates sodium dicarboxylate cotransporters (NaDCs) to move sodium and dicarboxylates [R(COO⁻)₂], such as α-ketoglutarate, into the cell. The resulting high intracellular concentration of dicarboxylates promotes uptake of OA across the basolateral membrane in exchange for [R(COO⁻)₂] by organic anion transporters (OAT1 and OAT3). Apical exit involves ABC transporters including multidrug-associated resistance proteins (MRP2, MRP4) and possibly other SLC transporters including OAT4 and urate transporter 1 (URAT1, not shown).

Figure 2.

Schematic of potential interactions between drugs, metabolites, and toxins due to competition for tubular secretion at the transporter level. (A) Some of the molecules that are transported by organic cation transporters (e.g., OCT2). Transport is inhibited by cimetidine and trimethoprim and by the novel pharmacoenhancer, cobicistat. (B) Some of the substrates for the organic anion transporters OAT1 and/or OAT3. Transport is inhibited by probenecid.

Figure 3.

Photomicrographs demonstrating tubular and cellular changes in wild-type (WT) and organic anion transporter 1 (Oat1) knockout kidneys upon exposure to mercuric chloride, HgCl₂. (A) In the wild-type kidney, substantial tubular damage was seen, as indicated by the dilated tubular lumen and flattened tubule epithelial cells, after a single dose of HgCl₂ (4 mg/kg body wt, intraperitoneal). (B) In contrast, the Oat1 knockout (Oat1KO) mice had normal tubules that appeared unaffected by mercury exposure. Although not shown, serum urea nitrogen levels increased significantly in the wild-type mouse but not in the knockout mouse with preserved tubules. (Adapted with permission from Torres et al. .)