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.

Grapefruit juice decreases exposure of aliskiren partially via inhibition of intestinal OATP1A2.

The purpose of the present study was to determine whether a physiologic plasma concentration of a-ketoglutarate (aKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular aKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and b-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular aKG competitively inhibited PAH and cidofovir transport with K i values (∼5 mM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular aKG (5 mM) significantly increased IC 50 values for some inhibitors (up to 4-fold), such as probenecid, but not for others (an inhibitor-dependent effect). For some inhibitors, a significant increase in IC 50 value was observed when cidofovir was the substrate, but not PAH (a substrate-dependent effect). A significant increase in IC 50 value was also observed for inhibition of PAH transport by probenecid in renal basolateral membrane vesicles (5.2-fold). The substrate-and inhibitor-dependent effect of extracellular aKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular aKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.