A plasma concentration of α-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1.
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.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
Leslie
L
Ingraham
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
Mansong
M
Li
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
J Larry
JL
Renfro
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
Sonda
S
Parker
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
Arpine
A
Vapurcuyan
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.).
Imad
I
Hanna
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (L.I., M.L., R.M.P.); Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (J.L.R., S.P.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey (A.V., I.H.) Ryan.pelis@dal.ca.
Ryan M
RM
Pelis
D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D000077404:Cidofovir; D003412:Cricetulus; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000097:blood* / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism*; D063065:Organophosphonates / Q000378:metabolism; D013552:Swine; D010130:p-Aminohippuric Acid / Q000378:metabolism
D007656:Ketoglutaric Acids; D008024:Ligands; D027361:Organic Anion Transporters; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir; D010130:p-Aminohippuric Acid