Journal
MOLECULAR PHARMACOLOGY
Volume 86, Issue 1, Pages 86-95Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.114.091777
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Funding
- Canadian Institutes of Health Research [286509]
- Nova Scotia Health Research Foundation [MED-EST-2013-9003]
- US National Science Foundation [0843253]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [0843253] Funding Source: National Science Foundation
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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.
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