Interactions of tetrapentylammonium (TPeA) with organic anion transporter 3 (Oat3) in rat choroid plexus (CP) and kidney slices

In rat CP, apical uptake of the H2 receptor antagonist and weak organic base, cimetidine, is inhibited by the organic anions, p‐aminohippurate (PAH) and estrone sulfate, not by the organic cation, tetraethylammonium (TEA), consistent with cimetidine transport on rOat3 (Nagata et al Drug Metab Disp 32:1040, 2004). Here we report that two larger organic cations, TBuA and TPeA inhibited cimetidine uptake; 100 μM TPeA inhibited by 50% and 1 mM by 85%. In CP, TPeA inhibited uptake of PAH on Oat3. To determine whether TPeA is transported on Oat3, we measured trans‐stimulation of 3H‐PAH efflux from CP. Addition of unlabeled PAH, glutarate or TPeA to the efflux medium significantly trans‐stimulated efflux. In rat renal cortical slices (which express rOat1 and rOat3), TPeA both inhibited PAH uptake and trans‐stimulated PAH efflux. In Xenopus oocytes expressing rOat3 or hOAT3, PAH uptake was inhibited by TPeA; no such inhibition was found in oocytes expressing rOat1 or hOAT1. Finally, millimolar concentrations of TEA did not affect PAH uptake or efflux in rat CP or renal slices or PAH uptake in Xenopus oocytes expressing rOat3, rOat1, hOAT3 or hOAT1. Thus, TPeA is both an inhibitor of and substrate for Oat3. This ability to interact with and transport a tetraalkylammonium must be a consideration when modeling the Oat3 substrate recognition site(s).