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 (TEA) 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. In contrast, larger, more hydrophobic organic cations, such as tributylmethylammonium (TBuMA), undergo significant hepatobiliary excretion. To better characterize hepatic organic cation transport, TBuMA transport was examined in rat canalicular liver plasma membrane (cLPM) and basolateral liver plasma membrane (bILPM) vesicles. In cLPM vesicles, under voltage-clamped conditions, an outwardly directed H+ gradient stimulated [3H]TBuMA uptake consistent with electroneutral TBuMA:H+ exchange; H(+)-dependent [3H]TBuMA uptake was not the result of a H+ diffusion potential. In the absence of a H+ gradient, intravesicular TBuMA trans-stimulated [3H]TBuMA uptake. Substrates for renal and hepatic organic cation:H+ exchange cis-inhibited H(+)-dependent [3H]TBuMA uptake. No ATP-dependent [3H]TBuMA uptake was detected in cLPM vesicles, and the P-glycoprotein substrate, daunomycin, did not cis-inhibit H(+)-dependent [3H]TBuMA uptake. Carrier-mediated [3H]TBuMA uptake exhibited saturability (Km of 0.5 mM and Vmax of 0.5 nmol/mg prot/5 s). In bILPM vesicles, in contrast, a valinomycin-induced intravesicular-negative K+ diffusion potential stimulated [3H]TBuMA uptake. These findings suggest that hepatic transport of TBuMA is similar to TEA but fundamentally different from that of P-glycoprotein substrates, indicating the involvement of at least two separate processes for the hepatobiliary excretion of organic cationic drugs.
Moseley
R H
RH
Department of Internal Medicine, Veterans Affairs Medical Center, Ann Arbor, Michigan, USA.
Smit
H
H
Van Solkema
B G
BG
Wang
W
W
Meijer
D K
DK
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D013757:Tetraethylammonium Compounds / Q000493:pharmacokinetics
D000644:Quaternary Ammonium Compounds; D013757:Tetraethylammonium Compounds; C043902:tri-n-butylmethylammonium; D000255:Adenosine Triphosphate