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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

Hong Soon Sun    (Department of Pharmaceutics, College of Pharmacy, Seoul National University   ); Li Hong    (Department of Pharmaceutics, College of Pharmacy, Seoul National University   ); Choi Min Koo    (Department of Pharmaceutics, College of Pharmacy, Seoul National University   ); Chung Suk Jae    (Department of Pharmaceutics, College of Pharmacy, Seoul National University   ); Shim Chang Koo    (Department of Pharmaceutics, College of Pharmacy, Seoul National University  );
  • 초록

    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 $\mu$ mol/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 ( $CL_b$ ) 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 ( $CL_{exc}$ ) 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 V $_{max}$ and $CL_{linear}$ , but the $K_m$ 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.


  • 참고문헌 (15)

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