Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver

Purpose. It has been shown that plasma concentration and urinary excretion of bile acids is elevated under the cholestatic/hyperbilirubinemic conditio ns. Previously, it was demonstrated that the plasma concentration of bile a cids was elevated in the multidrug resistance-associated protein 2 (Mrp2)-d eficient rats. The purpose of the present study was to compare the sinusoid al efflux clearance of taurocholate (TC) between Mrp2-deficient Eisai hyper bilirubinemic rats (EHBR) and normal rats. Method. Hepatic disposition of the [H-3]TC was examined in the perfused liv er. Apparent efflux clearance (PSnet, eff) of [H-3]TC from hepatocytes to o utflow across the sinusoidal membrane was defined as the amount of [H-3]TC excreted into the outflow from the liver divided by hepatic AUC of [H-3]TC. Additionally, influx clearance (PSinf) was also determined by multiple ind icator dilution method because PSnet, eff is also affected by PSinf. Results. PSnet, eff was significantly higher in EHBR than that in Sprague-D awley (SD) rats (16.6 +/- 1.7 vs. 6.1 +/- 1.3 muL/min/g liver, P <0.01). In contrast, PSinf was comparable between SD rats and EHBR. Kinetic analysis suggested that the intrinsic clearance for the efflux of [H-3]TC across the sinusoidal membrane in EHBR was higher than that in SD rats (10.4 +/- 1.0 v.s. 23.3 +/- 1.7 muL/min/g liver, P <0.01). Conclusions. Enhanced sinusoidal efflux of TC in EHBR may be related to til e altered disposition of bile acids in the mutant rats. Because Mrp3 transp orts TC and its expression is induced on the basolateral membrane of Mrp2-d eficient rats, the enhanced sinusoidal efflux of TC in EHBR may be accounte d for, at least partially, by the increased expression of Mrp3.