PHARMACOKINETIC ANALYSIS OF ENTEROHEPATIC CIRCULATION OF ETODOLAC ANDEFFECT OF HEPATIC AND RENAL INJURY ON THE PHARMACOKINETICS

This study was designed to evaluate the enterohepatic circulation of r acemic etodolac in rats. Additionally, the effect of hepatic and renal failure on the pharmacokinetics was estimated. The biliary excretion and the reabsorption of the drug excreted in bile were examined in ord er to clarify the effect of enterohepatic circulation on the dispositi on, and a pharmacokinetics model was applied to describe the enterohep atic circulation. The relatively rapid elimination of etodolac was see n in the bile-exteriorized rats (BE rat) compared with that in control rats, Total biliary excretion of etodolac, mainly as glucuronides, af ter intravenous administration was about 45% of the dose, indicating e xtensive enterohepatic circulation of the drug. The plasma concentrati ons of the drug in bile duct-linked rats approximately agreed with the simulation curve by the model, with the peak concentration 6-7 h afte r dosing. The elimination of the drug was markedly retarded in rats wi th hepatic (CCl4-induced) and renal (uranyl acetate-induced) failure, and high plasma levels were maintained over the longer times, due to g reatly decreased distribution volume, The biliary excretion of etodola c enantiomers was not significantly different between the control and CCl4-groups, suggesting that hepatic glucuronyl transferase activity w as preserved in rats impaired by CCl4.