The Role of the Kidney in Drug Elimination: Transport, Metabolism, and the Impact of Kidney Disease on Drug Clearance

Abstract

Recent advances in the identification and characterization of renal drug transporters and drug-metabolizing enzymes has led to greater understanding of their roles in drug and chemical elimination and in modulation of the intrarenal exposure and response to drugs, nephrotoxic compounds, and physiological mediators. Furthermore, there is increasing awareness of the potential importance of drug-drug interactions (DDIs) arising from inhibition of renal transporters, and regulatory agencies now provide recommendations for the evaluation of transporter-mediated DDIs. Apart from the well-recognized effects of kidney disease on renal drug clearance, there is a growing body of evidence demonstrating that the nonrenal clearances of drugs eliminated by certain transporters and drug-metabolizing enzymes are decreased in patients with chronic kidney disease (CKD). Based on these observations, renal impairment guidance documents of regulatory agencies recommend pharmacokinetic characterization of both renally cleared and nonrenally cleared drugs in CKD patients to inform possible dosage adjustment.