Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
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Altered Pharmacokinetics and Hepatic Uptake of TBuMA in Ethynylestradio-Induced Cholestasis

  • Hong Soon-Sun (Research Institute of Pharmaceutical Science & Department of Pharmaceutics, College of Pharmacy, Seoul National University) ;
  • Choi Jong-Moon (Research Institute of Pharmaceutical Science & Department of Pharmaceutics, College of Pharmacy, Seoul National University) ;
  • Jin Hyo-Eon (Research Institute of Pharmaceutical Science & Department of Pharmaceutics, College of Pharmacy, Seoul National University) ;
  • Shim Chang-Koo (Research Institute of Pharmaceutical Science & Department of Pharmaceutics, College of Pharmacy, Seoul National University)
  • Published : 2006.04.01
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Abstract

The objective of this study was to examine the pharmacokinetics of organic cations in intrahepatic cholestatic rats. A pretreatment with $17{\alpha}$-ethynylestradiol was used to induce intrahepatic cholestasis, and tributylmethylammonium (TBuMA) was used as a representative model organic cation. When $[^3H]$TBuMA was intravenously administered, the AUC value for TBuMA was significantly increased by $79\%$ in cholestasis, and its total systemic clearance was consequently decreased by $46\%$. In addition, the in vivo hepatic uptake clearance of TBuMA from the plasma to the liver was decreased by $50\%$ in cholestasis. The concentration of bile salts in plasma was increased by 2.1 fold in cholestatic rats. Since TBuMA forms ion-pair complexes with anionic components such as bile salts, the decreased hepatic uptake of TBuMA in cholestasis may be due to a change in endogenous components, e.g., bile salts in the plasma. In isolated normal hepatocytes, the uptake clearance for TBuMA in the presence of cholestatic plasma was decreased by $20\%$ compared with normal plasma. Therefore, we conclude that the inhibition of the hepatic uptake process by the cholestasis may be in part due to the increased formation of ion-pair complexes of TBuMA with bile salts in the plasma.

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References

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