Xenobiotic Transporters in the Kidney: Function and Role in Toxicity

Area of Science:

• Pharmacology
• Nephrology
• Toxicology

Background:

• The kidney eliminates xenobiotics, but drug-induced kidney injury (DIKI) is a significant risk in drug development.
• Accumulation of nephrotoxic compounds, mediated by xenobiotic transporters, often precedes kidney injury.
• Solute carrier (SLC) and ATP-binding cassette (ABC) transporters are critical in these processes.

Purpose of the Study:

• To review the current understanding of kidney transporters' role in toxic outcomes.
• To highlight knowledge gaps, particularly species differences affecting preclinical model predictivity.
• To detail the classification, physiological roles, and species variations of SLC and ABC transporters.

Main Methods:

• Review of existing literature on kidney transporters and DIKI.
• Analysis of mechanistic details of transporter-involved DIKI.
• Summary of preclinical (in vitro, in vivo) and clinical data utilization.
• Evaluation of conventional and emerging tools for studying kidney transporter function.

Main Results:

• Kidney transporters significantly influence xenobiotic elimination and nephrotoxicity.
• Species differences in transporter expression and function contribute to poor predictivity of animal models for human DIKI.
• Various experimental approaches are employed to study transporter roles in DIKI.

Conclusions:

• Improved understanding of kidney transporter function is essential for accurate DIKI risk assessment.
• Addressing species differences in transporter studies is critical for enhancing preclinical to clinical translation.
• Optimizing experimental approaches will advance the study of kidney transporters and their role in nephrotoxicity.