Functional characteristics of a renal H+/lipophilic cation antiport system in porcine LLC-PK1 cells and rats

We recently found the H + /quinidine (QND) antiport system in canine kidney MDCK and porcine kidney LLC-PK1 cells. The aims of the present study were to confirm the presence of the H + /QND antiport system in human embryonic kidney (HEK) 293 cells, and to investigate the substrate specificity of the system. The cellular uptake of 100 µM QND into HEK293 cells was decreased by acidification of extracellular pH and by NH4Cl-induced alkalization of intracellular pH. In addition, a lipophilic cationic drug, diphenhydramine (DPH), significantly decreased the QND uptake in HEK293 cells. In order to evaluate the substrate specificity of the renal H + /QND antiport system, we investigated the DPH-sensitive uptake (Δuptake) of 12 cationic compounds (celiprolol, acebutolol, procainamide, pindolol, bisoprolol, metoprolol, flecainide, clonidine, pyrilamine, QND, propranolol, and verapamil). The Δuptake positively correlated with their lipophilicity (Log D) values, and negatively correlated with their polar surface area (Log PSA) values. In contrast, the Δuptake did not correlate with their molar volume (MV), molar refractivity (MR), or polarization (PO). These findings indicate that an H + /QND antiport system is present in HEK293 cells, and that the Log D and Log PSA of drugs are important factors responsible for the transport activity of the postulated H + /lipophilic cation antiporter in the kidney.

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