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

• Published in: Molecular pharmacology 2014-07, Vol.86 (1), p.86-95
• Main Authors: Ingraham, Leslie, Li, Mansong, Renfro, J. Larry, Parker, Sonda, Vapurcuyan, Arpine, Hanna, Imad, Pelis, Ryan M.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological Transport - physiology; Cell Line; CHO Cells; Cricetulus; Cytosine - analogs & derivatives; Cytosine - metabolism; Humans; Ketoglutaric Acids - blood; Ketoglutaric Acids - metabolism; Kinetics; Ligands; Middle Aged; Organic Anion Transporters - metabolism; Organophosphonates - metabolism; p-Aminohippuric Acid - metabolism; Swine
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.114.091777

The purpose of the present study was to determine whether a physiologic plasma concentration of α-ketoglutarate (αKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular αKG 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 β-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular αKG competitively inhibited PAH and cidofovir transport with Ki values (∼5 μM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular αKG (5 μM) 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 αKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular αKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.