Approach to enhancing the distribution of glycyrrhizin in the liver: intravenous infusion studies in a rat model of bile duct ligation

We adopted a pharmaceutical approach to enhancing the distribution of glycyrrhizin (GZ) in the liver based on continuous administration of GZ for chronic hepatitis therapy. The present study characterizes the changes in GZ concentration in serum, bile, and liver under steady-state conditions after drip GZ infusion (0.5-2.0 mg/ml/h) in rats with bile duct fistulas. Eight hours after infusion, approximately 90% of GZ was excreted into bile as an intact compound regardless of the GZ dose tested. We observed a non-linear relationship between steady-state serum GZ concentrations and GZ dose (i.e. serum GZ concentrations abruptly increased with increasing GZ dose). GZ concentrations in the liver 8 h after infusion paralleled those in serum under steady-state conditions, but did not parallel those in bile. These results led us to conclude that under our experimental conditions transport activity responsible for the excretion of GZ to bile was in a rate-limiting step compared to that responsible for the uptake of GZ by hepatocytes. We therefore predicted that GZ concentration in the liver will increase with obstructing an efflux transport system such as canalicular multi-specific organic anion transporters. Probenecid among inhibitors or substrates for efflux transporters significantly enhanced the liver GZ concentration in the infusion studies. In conclusion, the concomitant administration of probenecid would be useful for liver protection therapy under continuous injection of the limited amount of GZ.