Inhibitory Effect of Pentobarbital on Biliary Excretion of Diclofenac in a Rat Liver Perfusion System

Abstract

Abstract The effect of pentobarbital on the biliary excretion of diclofenac was investigated in a rat liver perfusion system following a pulse input of the drug. Without albumin in the perfusate, a trace amount of diclofenac was detected in the outflow from the liver (< 0.1%). The total biliary excretion of diclofenac (intact diclofenac plus its glucuronide) decreased from 23.8% (diclofenac 6.01, glucuronide 17.8%) to 16.3% (diclofenac 5.09, glucuronide 11.2%) with an increase in the perfusate concentration of pentobarbital from 0 to 2.5 μg mL−1. At pentobarbital concentrations exceeding 2.5 μg mL−1, the biliary excretion of diclofenac and its glucuronide (14% total diclofenac) was not reduced further. The mean local excretion times of both diclofenac and its glucuronide were approximately 17 min and were unchanged at all pentobarbital concentrations tested. The ratios of biliary excreted diclofenac and its glucuronide to total diclofenac were 22 and 78%, respectively, and these values were virtually constant at all concentrations of pentobarbital in the perfusate. These results suggest that the glucuronidation of diclofenac and the biliary excretion of its glucuronide are rapid processes and that pentobarbital blocks a step before glucuronidation.