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A plasma concentration of α-ketoglutarate 1 influences the kinetic interaction of ligands with OAT1

Vapurcuyan, Arpine and Hanna, Imad and Pelis, Ryan and Renfro, Larry and Ingraham, Leslie and Parker, Sonda (2014) A plasma concentration of α-ketoglutarate 1 influences the kinetic interaction of ligands with OAT1. Molecular Pharmacology.

Abstract

Despite the importance of extracellular α-ketoglutarate ( 54 αKG) for OAT1 transport in
vivo, in vitro studies to assess drug-drug interaction (DDI) potential at OAT1 are conducted in its
absence. The purpose was to determine if a physiological plasma concentration of αKGinfluences the kinetic interaction of ligands with OAT1 in vitro. 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 ten drugs in five different classes to inhibit OAT1 expressed in
Chinese Hamster Ovary cells. Extracellular αKG competitively inhibited PAH and cidofovir transport with Ki values (~5 μM) approximating the unbound plasma concentration (determined
by equilibrium dialysis). Extracellular αKG (5 μM) increased IC50 values (up to 4-fold) for
some inhibitors, but not others. Whereas a significant increase in IC50 value against PAH
transport was observed for probenecid (2.3-fold), naproxen (2.3-fold) and cephalothin (2.8-fold)
there was only a significant increase in IC50 for naproxen (2.5-fold) when cidofovir was the
substrate. An increase in IC50 value (5.8-fold) was also observed for inhibition of PAH transport
by probenecid in renal basolateral membrane vesicles. We contend that in vitro kinetic
interactions of ligands with OAT1 will be more reflective of the in vivo interactions if the in
vitro studies are done in the presence of a plasma level of αKG. Conducting in vitro kinetic
inhibition studies in the presence of a plasma concentration of αKG should improve the accuracy
of DDI predictions at OAT1.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/20150

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