Altered pharmacokinetics and hepatic uptake of TBuMA in ethynylestradiol-induced cholestasis.

The objective of this study was to examine the pharmacokinetics of organic cations in intrahepatic cholestatic rats. A pretreatment with 17alpha-ethynylestradiol was used to induce intrahepatic cholestasis, and tributylmethylammonium (TBuMA) was used as a representative model organic cation. When [3H]TBuMA was intravenously administered1 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.