Research Methods and New Advances in Drug-Drug Interactions Mediated by Renal Transporters

Abstract

The kidney is critical in the human body's excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug-drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro-in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject's situation when they are going to study DDIs mediated by renal transporters.

Keywords: analytical tools; drug–drug interactions; model; renal transporter.

Figure 1

Major drug transporters in proximal tubular cells of the kidney: OAT1—organic anion transporter 1; OAT3—organic anion transporter 3; OAT4—organic anion transporter 4; OATP4C1—organic anion transporter polypeptide 4C1; OCT2—organic cation transport 2; OCT3—organic cation transport 3; PEPT2—peptide transporter 2; MATE1—multidrug and toxin extrusion protein 1; MATE2-K—multidrug and toxin extrusion protein 2 kidney-specific; MRP2—multidrug resistance-associated protein 2; MRP4—multidrug resistance-associated protein 4; P-gp—P-glycoprotein; BCRP—breast cancer-resistance protein; OCTN1—organic cation/carnitine transport 1; OCTN2—organic cation/carnitine transport 2. Efflux transporters/carriers highlighted in purple, influx carriers in blue, and bidirectional carriers in gray.

Figure 2

Models for transporter-mediated DDI studies. IVIVE—In vitro–in vivo extrapolation; EVKP—Ex vivo kidney perfusion; PET technology—Positron emission tomography technology; MLMs—machine learning methods; PBPK—physiologically based pharmacokinetic.