Effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of organic cations (OCs): selective inhibition of sinusoidal OCs uptake without influencing glucose uptake and canalicular OCs excretion.

The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 micromol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance (CLb) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane (CLexc) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent Vmax and CLlinear, but the Km for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.