Renal Drug Transport and Drug-Drug Interactions

Abstract

The kidney plays a vital role in the elimination of xenobiotics including drugs, toxins, and endogenous metabolites. Renal drug elimination involves 3 major processes: glomerular filtration, tubular secretion, and tubular reabsorption. Although glomerular filtration is a simple unidirectional diffusion process, renal tubular secretion and/or reabsorption can involve saturable processes mediated by multiple highly specialized membrane transport systems. Current research has identified that these transport proteins play a significant role in the efficient removal and/or reabsorption of pharmacological agents. Since the majority of membrane transporters have broad substrate specificity, there is a significant risk for drug-drug interactions through competition for similar transport pathways. This article will focus on the cellular expression, localization, and transport properties of various renal drug transport systems (ie, organic anion, organic cation, nucleoside, and adenosine triphosphate [ATP]-dependent efflux transporters). Specific examples of drugs that are transported by each of these mechanisms will be provided. Clinically relevant drug-drug interactions involving renal drug transporters will be discussed to guide the clinician in understanding and preventing these interactions.

Absence of a Pharmacokinetic Interaction Between Entecavir and Adefovir

“…The lack of a drug‐drug interaction between adefovir and entecavir could well be attributed to the existence of multiple transport systems with different substrate specificities. In addition, many nucleosides and nucleoside analog drugs are substrates for more than 1 transport protein 14 . These different transport proteins include organic anion transporters (OAT), organic cation transporters, and P‐glycoprotein (P‐gp).…”

The search for nucleoside/nucleotide analog inhibitors of dengue virus

“…This could cause renal toxicity, especially when two drugs use the same transporter for elimination (Cihlar et al, 2009;Ronaldson and Bendayan, 2002). Drug-drug interaction is also likely to occur when two nucleoside inhibitors are phosphorylated by the same enzyme (Kewn et al, 1997).…”