A Plasma Concentration of alpha-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

作者：Ingraham Leslie; Li Mansong; Renfro J Larry; Parker Sonda; Vapurcuyan Arpine; Hanna Imad; Pelis Ryan M^*

来源：Molecular Pharmacology, 2014, 86(1): 86-95.

DOI：10.1124/mol.114.091777

The purpose of the present study was to determine whether a physiologic plasma concentration of alpha-ketoglutarate (alpha KG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular alpha KG 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 beta-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular alpha KG competitively inhibited PAH and cidofovir transport with K-i values (similar to 5 mu M) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular aKG (5 mu M) significantly increased IC50 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 IC50 value was observed when cidofovir was the substrate, but not PAH (a substrate-dependent effect). A significant increase in IC50 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 alpha KG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular alpha KG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.

• 出版日期2014-7