Inhibitors of prolyl hydroxlase are substrates of the organic anion transporter 1 (OAT1)

Impaired oxygen delivery induces hypoxia‐inducible transcription factors (HIFs). Stability of HIFs is mediated by prolyl‐4‐hydroxylases (PHDs). α‐Ketoglutarate (áKG) analogues were used as PHD inhibitors and stabilized HIF. Uptake of áKG in proximal tubule cells is mediated by the basolaterally located sodium‐dicarboxylate cotransporter 3 (NaDC3) and the organic anion transporters 1 and 3 (OAT1, OAT3). Release of áKG occurs via luminal OAT4. We examined the interaction of the PHD inhibitors N‐oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4‐diethylpyridine dicarboxylate (2,4‐DPD), and pyridine‐dicarboxylic acid (PDCA) with NaDC3, OAT1, OAT3, and OAT4. While NOG, DMOG, 2,4‐DPD, and PDCA did not interact with NaDC3, OAT3, and OAT4, uptake of p‐aminohippurate by OAT1 was inhibited by NOG, 2,4‐DPD, and PDCA with an Ki of 353, 38, and 20 μM, respectively. By Western blotting, stabilization of HIF by NOG and PDCA could be demonstrated selectively in OAT1‐transfected cells, suggesting that these compounds are taken up by OAT1. Thus, OAT1 is a pharmaceutical target for PHD inhibitors.