Human and rat renal proximal tubule in vitro models for ADME applications

The kidney is a major organ dictating excretion rates of chemicals and their metabolites from the body and thus renal clearance is frequently a major component of pharmaco-(toxico)-kinetic profiles. Within the nephron, the proximal tubule is the major site for xenobiotic reabsorption from glomerular filtrate and xenobiotic secretion from the blood into the lumen via the expression of multiple inward (lumen to interstitium) and outward transport systems (interstitium to lumen). While there exist several human proximal tubular cell culture options that could be utilized for modelling the proximal tubule component of renal clearance, they do not necessarily represent the full complement of xenobiotic transport processes of their in vivo counterparts. Here, we review available human and rat renal proximal tubule in vitro models, including subcellular fractions, immortalized cell lines, primary cell cultures, induced pluripotent stem cell (iPSC)-derived models and also consider more organotypic cell culture environments such as microporous growth supports, organoids and microfluidic systems. This review focuses on expression levels and function of human and rat renal transporters and phase I and II metabolizing enzymes in these models in order to critically assess their usefulness and to identify potential solutions to overcome identified limitations.