S S Hong1, S J Chung, C K Shim. 1. Department of Pharmaceutics, College of Pharmacy, Seoul National University, Korea.
Abstract
PURPOSE: The effect of CCl4-induced experimental hepatic failure (EHF) on the sequential hepatobiliary transport of model organic cations (OCs), triethylmethylammonium (TEMA), and tributylmethylammonium (TBuMA), was investigated in rats. METHODS: EHF was induced by an i.p. injection of CCl4 at a dose of 1 ml/kg 24 hr prior to the transport study. The cumulative in vivo biliary excretion, in vitro hepatic uptake by isolated hepatocytes, in vitro efflux (i.e., release) from hepatocytes, and in vivo hepatobiliary excretion clearance were measured for normal and CCl4-EHF rats. RESULTS: The CCl4-EHF decreased the apparent in vivo biliary clearance (CL(b)) and the in vitro maximum uptake rate (Vmax, uptake) of TBuMA by 66 and 48%, respectively. The CCl4-EHF had no effect on the CL(b) of TEMA. but decreased both the Vmax, uptake (59%) and the in vitro maximum hepatic efflux rate (Vmax, efflux) of TEMA (80%). On the contrary, the CCl4-EHF had no influence on the in vivo hepatobiliary excretion clearance (CL(exc)) of both OCs. CONCLUSIONS: Transport systems for the OCs on the sinusoidal membrane (uptake and/or efflux), rather than those on the bile canalicular membrane (excretion) appear to be prone to damage by the CC14-EHF.
PURPOSE: The effect of CCl4-induced experimental hepatic failure (EHF) on the sequential hepatobiliary transport of model organic cations (OCs), triethylmethylammonium (TEMA), and tributylmethylammonium (TBuMA), was investigated in rats. METHODS: EHF was induced by an i.p. injection of CCl4 at a dose of 1 ml/kg 24 hr prior to the transport study. The cumulative in vivo biliary excretion, in vitro hepatic uptake by isolated hepatocytes, in vitro efflux (i.e., release) from hepatocytes, and in vivo hepatobiliary excretion clearance were measured for normal and CCl4-EHF rats. RESULTS: The CCl4-EHF decreased the apparent in vivo biliary clearance (CL(b)) and the in vitro maximum uptake rate (Vmax, uptake) of TBuMA by 66 and 48%, respectively. The CCl4-EHF had no effect on the CL(b) of TEMA. but decreased both the Vmax, uptake (59%) and the in vitro maximum hepatic efflux rate (Vmax, efflux) of TEMA (80%). On the contrary, the CCl4-EHF had no influence on the in vivo hepatobiliary excretion clearance (CL(exc)) of both OCs. CONCLUSIONS: Transport systems for the OCs on the sinusoidal membrane (uptake and/or efflux), rather than those on the bile canalicular membrane (excretion) appear to be prone to damage by the CC14-EHF.