Influence of laparotomy on disposition kinetics of diclofenac in CCl4-intoxicated rats.

Abstract

The effect of the acute hepatic failure induced by CCl4 on the pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation (EHC) in normal rats, was evaluated. This hepatic failure extinguished the secondary peak on the plasma time course which is usually observed in normal rats due to EHC. In the group without EHC by means of bile cannulation, the total clearance (CL) markedly decreased by CCl4-intoxication from 0.7 l/h/kg down to 0.1 l/h/kg, and mean residence time (MRT) increased from 0.29 h up to 2.8 h. The plasma time curves of the rats with laparotomy and with bile duct-cannulation were almost the same in the CCl4-intoxicated group. The bile excretion ratio of diclofenac markedly decreased by CCl4-intoxication from 43% down to 13%. In both groups, 92% of the total diclofenac excreted into the bile was glucuronide. While EHC made area under the curve (AUC) and MRT obviously increase in the CCl4-free rats, the effect of EHC on these moments was negligible in the CCl4-intoxicated rats. In the CCl4-intoxicated condition, the elimination of diclofenac in the rats with laparotomy was considerably slower than that in the rats without laparotomy. The plasma time courses were obviously monoexponential in the former group, while those were almost biexponential in the latter group.