Multiple transport systems for organic anions across the bile canalicular membrane

Multiplicity for the transport of organic anions across the bile canalicular membrane was studied in vivo and in vitro using dibromosulfophthalein (DBSP), [14C]cefodizime, [3H]leukotriene C4 (LTC4) and indocyanine green (ICG) as model compounds in rats. A high concentration of DBSP in plasma reduced the biliary excretion of cefodizime and leukotriene radioactivity to about 15 and 35% of their control values, respectively, but did not affect the excretion of ICG. A high plasma concentration of ICG reduced the excretion of cefodizime to about 60% of the control value, but exerted minimal effect on the excretion of leukotriene radio-activity and DBSP. In vitro, ATP-dependent uptake of LTC4 into the canalicular membrane vesicles was reduced by DBSP, cefodizime and ICG in a dose-dependent manner, with approximate IC50 values of 0.1 microM, 10 microM, and 1 microM, respectively. The hepatic unbound concentration of DBSP sufficient to reduce the excretion of cefodizime, leukotriene radioactivity and DBSP itself in vivo was calculated to be approximately 10 microM, a concentration which was also sufficient to reduce the transport of LTC4 in vitro. In contrast, the hepatic unbound concentration of ICG that saturated the excretion of ICG in vivo was calculated to be less than 0.1 microM, which was more than ten times smaller than the IC50 of ICG for the transport of LTC4 in vitro. These results suggest the presence of multiple systems for the transport of organic anions across the bile canalicular membrane: one is the predominant transport system for DBSP and cefodizime, which also accepts LTC4 as a substrate; the other is the primary transport system for ICG, which is distinct from that for DBSP, cefodizime and LTC4, although some overlap in the substrate specificity may be observed between the two systems.