Loading-Washout Studies of the Stereoselective Sinusoidal Uptake of (R)- and (S)-2-Phenylpropionyl Acyl Glucuronide

Abstract

The vectorial movement of glucuronide conjugates from blood into bile can be an important elimination route for many drug metabolites, however the intrinsic hydrophilicity of those conjugates may conceptually act to reduce the overall efficiency of that process by limiting the flux of such conjugates across the sinusoidal membrane domain of hepatocytes. In this investigation, the hepatic disposition of the diastereomeric glucuronides of (R)- and (S)-2-phenylpropionic acid (a model "profen" compound) have been studied using the isolated perfused rat liver to establish whether a permeability barrier at the sinusoidal membrane domain (demonstrated previously for those conjugates) is of a sufficient magnitude to impact on the overall biliary excretion of these conjugates. Livers were perfused (30 mL/min) with perfusate containing either (R)-PPA, (S)-PPA, (R)-PPA-Glucuronide or (S)-PPA-Glucuronide in order to determine the dispositional profile of each glucuronide administered to the liver as both a preformed and an hepatically-generated metabolite. Once an apparent steady-state condition had been reached, infusion of test compound was ceased in order to establish the kinetics of the hepatic washout. The extent of biliary excretion of each glucuronide was dependent upon whether the glucuronide was presented to the liver as a preformed or hepatically-generated metabolite, and those differences, when analysed using a physiologically-based pharmacokinetic model, were consistent with the sinusoidal membrane acting as a barrier to the cellular entry of the glucuronides. Furthermore, that barrier was more pronounced for (R)-PPAG than it was for (S)-PPAG, suggesting that the hepatocellular uptake of the two diastereomers is stereoselective.