Abstract
The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell–derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive “human-like” in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future.
Footnotes
- Received June 7, 2018.
- Accepted August 1, 2018.
P.B., S.K.C., R.Y., and G.X. are compensated employees of Takeda Pharmaceutical Company Limited. E.J.K. was supported in part by the National Institutes of Health [Grants UH3TR000504, UG3TR002158, and ES070033] and by the Environmental Protection Agency Assistance Agreement [Grant 83573801].
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics