MECHANISMS FOR THE HEPATIC-UPTAKE AND BILIARY-EXCRETION OF TRIBUTYLMETHYLAMMONIUM - STUDIES WITH RAT-LIVER PLASMA-MEMBRANE VESICLES

Hepatic organic cation transport in vitro, using tetraethylammonium (T EA) as a substrate, consists of at least two steps: sinusoidal uptake is stimulated by an inside-negative membrane potential and canalicular membrane transport is mediated by organic cation:H+ exchange (Moseley et al., 1992b). In vivo, however, TEA is poorly excreted into bile. I n contrast, larger, more hydrophobic organic cations, such as tributyl methylammonium (TBuMA), undergo significant hepatobiliary excretion. T o better characterize hepatic organic cation transport, TBuMA transpor t was examined in rat canalicular liver plasma membrane (cLPM) and bas olateral liver plasma membrane (blLPM) vesicles. In cLPM vesicles, und er voltage-clamped conditions, an outwardly directed H+ gradient stimu lated [H-3]TBuMA uptake consistent with electroneutral TBuMA:H+ exchan ge; H+-dependent [H-3]TBuMA uptake was not the result of a H+ diffusio n potential. In the absence of a H+ gradient, intravesicular TBuMA tra ns-stimulated [H-3]TBuMA uptake. Substrates for renal and hepatic orga nic cation:H+ exchange cis-inhibited H+-dependent [H-3]TBuMA uptake. N o ATP-dependent [H-3]TBuMA uptake was detected in cLPM vesicles, and t he P-glycoprotein substrate, daunomycin, did not cis-inhibit H+-depend ent [H-3]TBuMA uptake. Carrier-mediated [H-3]TBuMA uptake exhibited sa turability (K-m of 0.5 mM and V-max of 0.5 nmol/mg prot/5 s). In blLPM vesicles, in contrast, a valinomycin-induced intravesicular-negative K+ diffusion potential stimulated [H-3]TBuMA uptake. These findings su ggest that hepatic transport of TBuMA is similar to TEA but fundamenta lly different from that of P-glycoprotein substrates, indicating the i nvolvement of at least two separate processes for the hepatobiliary ex cretion of organic cationic drugs.