Contribution of ion-pair complexation with bile salts to the transport of organic cations across LLC-PK1 cell monolayers.

Abstract

To examine the effect of ion-pair complexation with endogenous bile salts on the transport of organic cations (OCs) across LLC-PK1 cell monolayers. The transport of tributylmethyl-ammonium (TBuMA) and triethylmethylammonium (TEMA) across the cell monolayer was measured in the presence of taurodeoxycholate (TDC), an endogenous organic anion that forms an ion-pair complex with TBuMA, but not with TEMA. Under proton gradient conditions (i.e., pH 6.0 apical/pH 7.4 basal), the above OCs exhibited similar transport charactersistics, consistent with the well-established OC/H+ antiporter, and the presence of TDC had no measurable effect on the transport of these OCs. Under pH-equilibrated conditions (i.e., pH 7.4 apical/pH 7.4 basal); however. basal to apical transport of TBuMA, not that of TEMA, was increased in the presence of TDC, probably as a result of the formation of a lipophilic ion-pair complex between TBuMA and TDC. The transport and efflux of the TBuMA-TDC complex across the apical membrane of the cell was inhibited by representative substrates of the P-glycoprotein (P-gp), indicating the involvement of P-gp in this process. The increased affinity of the ion-pair complex to P-gp is consistent with a mechanism involving increased transport. In cases where there is no proton gradient between the plasma and urine, the formation of lipophilic ion-pair complexes in the kidney with endogenous bile salts might be involved in the in vivo urinary excretion of large Mw OCs, such as TBuMA.