Statistical Moment Analysis of Hepatobiliary Transport of Phenol Red in the Perfused Rat Liver

Abstract

A new experimental system was applied to study hepatobiliary transport of drugs. Rat livers were perfused using a single-pass technique, and phenol red was momentarily introduced to this system from the portal side. Outflow dilution patterns of phenol red were analyzed using statistical moment theory, and kinetic parameters of hepatic distribution and elimination of phenol red were calculated from moments, namely, the hepatic extraction ratio (E _i) and elimination rate constant (k _el,i). A larger distribution volume (V _i) was obtained for phenol red than for ¹³¹I-human serum albumin (HSA) and ⁵¹Cr-red blood cells (RBC), indicating its extravascular diffusivity. The biliary excretion of conjugated phenol red was delayed relative to that of the free agent. The larger biliary mean transit time (t _bile,conj.) represents the processes of biliary transport and intrahepatic metabolism. Further, the effects of dose and perfusion temperature on the hepatobiliary transport of phenol red were determined. With high doses or low perfusion temperatures (20 and 27°C), E _i, k _el,i, and intrinsic clearance (CL_int,i) of phenol red and biliary recovery of free and conjugated phenol red (F _bile,free, F _bile,conj) significantly decreased. The temperature-dependent and saturable processes in hepatic uptake, metabolism, and biliary excretion of phenol red were assessable to moment analysis.