Pharmacokinetic analysis of enterohepatic circulation of etodolac and effect of hepatic and renal injury on the pharmacokinetics.
This study was designed to evaluate the enterohepatic circulation of racemic 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 order to clarify the effect of enterohepatic circulation on the disposition, and a pharmacokinetics model was applied to describe the enterohepatic circulation. The relatively rapid elimination of etodolac was seen in the bile-exteriorized rats (BE rat) compared with that in control rats. Total biliary excretion of etodolac, mainly as glucuronides, after intravenous administration was about 45% of the dose, indicating extensive enterohepatic circulation of the drug. The plasma concentrations of the drug in bile duct-linked rats approximately agreed with the simulation curve by the model, with the peak concentration 6-7 h after dosing. The elimination of the drug was markedly retarded in rats with hepatic (CCI4-induced) and renal (uranyl acetate-induced) failure, and high plasma levels were maintained over the longer times, due to greatly decreased distribution volume. The biliary excretion of etodolac enantiomers was not significantly different between the control and CCI4-groups, suggesting that hepatic glucuronyl transferase activity was preserved in rats impaired by CCI4.
Ogiso
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
Kitagawa
T
T
Iwaki
M
M
Tanino
T
T
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D004764:Enterohepatic Circulation; D017308:Etodolac / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009942:Organometallic Compounds / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009942:Organometallic Compounds; C005460:uranyl acetate; D017308:Etodolac; D002251:Carbon Tetrachloride