Expression of Organic Anion Transporter 2 in the Human Kidney and Its Potential Role in the Tubular Secretion of Guanine-Containing Antiviral Drugs

Abstract

ABSTRACT:The organic anion transporters 1 and 3 (OAT1 and OAT3) and organic cation transporter 2 (OCT2) are important for renal tubular drug secretion. In contrast, evidence for OAT2 expression in the human kidney is limited, and its role in renal drug transport is unknown. Both mRNA (real-time polymerase chain reaction) and protein (Western blotting) for OAT2 were detected in renal cortex from eight donors, and interindividual variability in protein levels was 3-fold. OAT2 protein in the renal cortex was localized (by immunohistochemistry) to the basolateral domain of tubules, as were OAT1 and OAT3. The absolute abundance of OAT2 mRNA was similar to that of OAT1 mRNA and 3-fold higher than that of OCT2 mRNA but 10-fold lower than that of OAT3 mRNA. A previous observation that OAT2 transports cGMP led us to examine whether acyclovir, ganciclovir, and penciclovir are OAT2 substrates; they are guanine-containing antivirals that undergo active tubular secretion. Transport of the antivirals into human embryonic kidney cells was stimulated 10-to 20-fold by expression of OAT2, but there was little to no transport of the antivirals by OAT1, OAT3, or OCT2. The K m values for acyclovir, ganciclovir, and penciclovir transport were 94, 264, and 277 M, respectively, and transport efficiencies were relatively high (6-24 l ⅐ min ؊1 ⅐ mg protein ؊1 ).This study provides definitive evidence for the expression of OAT2 in the human kidney and is the first to demonstrate that OAT2, compared with OAT1, OAT3, or OCT2, has a preference for antiviral drugs mainly eliminated in the urine via active secretion.

The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

“…OAT2 has many substrates in common with OAT1 and OAT3. However, several antiviral drugs eliminated exclusively in the urine were preferentially transported by OAT2 and not by OAT1 and OAT3 (Cheng et al, 2012). OAT1, OAT2, and OAT3 mRNAs are present in the human kidney cortex, with the highest mRNA level observed for OAT3, and different mRNA levels for OAT1 and OAT2 in two separate reports (Motohashi et al, 2002;Cheng et al, 2012).…”

“…In contrast to OAT1 and OAT3, the role of OAT2 is less well characterized. More studies have emerged this decade focusing on OAT2 expression in the human kidney as well as its role in renal tubular handling of drugs (Cheng et al, 2012;Lepist et al, 2014;Shen et al, 2015). OAT2 is expressed in the basolateral membrane of renal proximal tubule cells as well as in the sinusoidal membrane of hepatocytes (Kobayashi et al, 2005;Cheng et al, 2012).…”

“…More studies have emerged this decade focusing on OAT2 expression in the human kidney as well as its role in renal tubular handling of drugs (Cheng et al, 2012;Lepist et al, 2014;Shen et al, 2015). OAT2 is expressed in the basolateral membrane of renal proximal tubule cells as well as in the sinusoidal membrane of hepatocytes (Kobayashi et al, 2005;Cheng et al, 2012). One group showed that OAT2 was localized in both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but only in the apical membrane of rat proximal tubules (Shen et al, 2015).…”

Impact on Creatinine Renal Clearance by the Interplay of Multiple Renal Transporters: A Case Study with INCB039110

“…It was indeed feasible to transfect MDCK-II monolayers with all five transporters and is herein referred to as the quintuple model. The relative amounts of DNAs used in transfection were aimed to approximate the relative expression levels of the transporters in human kidney (Nishimura and Naito, 2005;Cheng et al, 2012;Morrissey et al, 2012). Reports on the relative mRNA levels of OAT2 and OCT2 are conflicting; therefore, these two transporters were expressed at similar levels in the quintuple transporter model.…”

Telaprevir and Ribavirin Interaction: Higher Ribavirin Levels Are Not Only Due to Renal Dysfunction during Triple Therapy

“…To our knowledge, it is unknown whether Rbv is eliminated only by glomerular filtration or by tubular secretion as well. However, this is a plausible hypothesis, as other nucleoside analogues undergo tubule-mediated elimination by different organic anion and cation transporters and multidrug and toxin extrusion proteins (32)(33)(34)(35).…”