Altered pharmacokinetics and hepatic uptake of TBuMA in ethynylestradio-induced cholestasis

• Published in: Archives of pharmacal research Vol. 29; no. 4; pp. 323 - 327
• Main Authors: Hong, Soon-Sun, Choi, Jong-Moon, Jin, Hyo-Eon, Shim, Chang-Koo
• Format: Journal Article
• Language: English
• Published: 대한약학회 01.04.2006
• Subjects: bile salts; cations; hepatocytes; intrahepatic cholestasis; intravenous injection; liver; pharmacokinetics; rats; tritium; 약학
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/BF02968578

The objective of this study was to examine the pharmacokinetics of organic cations in intrahepatic cholestatic rats. A pretreatment with 17α-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, thein 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.