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Background  Knowledge of the molecular basis and transport function of the human blood–brain barrier (BBB) is important for not only understanding human cerebral physiology, but also development of new central nervous system (CNS)-acting drugs. However, few studies have been done using human brain capillary endothelial cells, because human brain materials are difficult to obtain. The purpose of this study is to clarify the functional expression of a proton-coupled organic cation (H + /OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, which has been recently developed as an  in vitro  human BBB model.    Methods  Diphenhydramine, [ 3 H]pyrilamine and oxycodone were used as cationic drugs that proved to be H + /OC antiporter substrates. The  in vitro  uptake experiments by hCMEC/D3 cells were carried out under several conditions.    Results  Diphenhydramine and [ 3 H]pyrilamine were both transported into hCMEC/D3 cells in a time- and concentration-dependent manner with K m  values of 59 μM and 19 μM, respectively. Each inhibited uptake of the other in a competitive manner, suggesting that a common mechanism is involved in their transport. The diphenhydramine uptake was significantly inhibited by amantadine and quinidine, but not tetraethylammonium and 1-methyl-4-phenylpyridinium (substrates for well-known organic cation transporters). The uptake was inhibited by metabolic inhibitors, but was insensitive to extracellular sodium and membrane potential. Further, the uptake was increased by extracellular alkalization and intracellular acidification. These transport properties are completely consistent with those of previously characterized H + /OC antiporter in rat BBB.    Conclusions  The present results suggest that H + /OC antiporter is functionally expressed in hCMEC/D3 cells.

fluids and barriers of the cns

Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood–brain barrier model