PT  - JOURNAL ARTICLE
AU  - Leslie Ingraham
AU  - Mansong Li
AU  - J. Larry Renfro
AU  - Sonda Parker
AU  - Arpine Vapurcuyan
AU  - Imad Hanna
AU  - Ryan M. Pelis
TI  - A Plasma Concentration of <em>α</em>-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1
AID  - 10.1124/mol.114.091777
DP  - 2014 Jul 01
TA  - Molecular Pharmacology
PG  - 86--95
VI  - 86
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/86/1/86.short
4100  - http://molpharm.aspetjournals.org/content/86/1/86.full
SO  - Mol Pharmacol2014 Jul 01; 86
AB  - 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.