Functional impairment of sinusoidal membrane transport of organic cations in rats with CCI₄-induced hepatic failure

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 (V(max, uptake)) of TBuMA by 66 and 48%, respectively. The CCl₄-EHF had no effect on the CL(b) of TEMA, but decreased both the V(max, uptake) (59%) and the in vitro maximum hepatic efflux rate (V(max, efflux)) of TEMA (80%). On the contrary, the CCl₄-EHF had no influence on the in viva 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 CCl₄-EHF.