Abstract
The aims of the present study were to evaluate whether the postulated H+/tertiary amine antiporter is expressed in human intestinal HT-29 cells as well as other cell lines, Caco-2 and LS180, and to identify the factor(s) of the uptake activity of the postulated H+/tertiary amine antiporter in the intestine. The profile of extracellular and intracellular pH-dependent uptake of quinidine, a substrate for the postulated H+/tertiary amine antiporter, into HT-29 cells was consistent with that in Caco-2 and LS180 cells. In addition, the uptake of quinidine into Caco-2, LS180, and HT-29 cells was significantly inhibited by diphenhydramine, a potent inhibitor of the postulated H+/tertiary amine antiporter, suggesting that the postulated H+/tertiary amine antiporter may be expressed in HT-29 cells. The diphenhydraminesensitive uptake (Δuptake) of 12 cationic compounds (celiprolol, acebutolol, pindolol, bisoprolol, metoprolol, propranolol, procainamide, quinidine, flecainide, clonidine, pyrilamine, and verapamil) into LS180 cells was positively correlated with their lipophilicity (Log D) values. In addition, there was a moderate negative correlation between the Δuptake of cationic compounds and their Log polar surface area (PSA) values. The predicted Δuptake values estimated by the Log D and Log PSA values fitted well with the observed values. These findings suggest that the lipophilicity and PSA of cationic compounds are factors of the uptake activity of these compounds by the postulated H+/tertiary amine antiporter in the intestine.
