The pharmacokinetics of etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers

DR Brocks and F Jamali

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.

Pharmacokinetics of the enantiomers of the nonsteroidal anti- inflammatory drug etodolac (ET, (+/- )-1,8-diethyl-1,3,4,9- tetrahydropyrano[3,4-b]indole-1-acetic acid), which is marketed as a racemate, were studied in male Sprague-Dawley rats. Following administration of iv racemate, plasma concentrations of inactive R-ET were much greater than those of active S-ET. After iv doses of individual enantiomers, similar results were found, with significantly greater t1/2, CL, and Vdss, and lower AUC, for S- than for R-ET. No evidence of a pharmacokinetic interaction between the enantiomers was observed. Secondary peaks indicative of extensive enterohepatic recirculation were seen in plasma time courses of S-ET. In bile duct- cannulated rats, the AUC of S- but not R-ET, was significantly reduced, and secondary peaks were absent in plasma profiles. The differences between enantiomers were attributed to a greater extent of plasma protein binding of R-ET, and to preferential conjugation and biliary excretion of S-ET. Complete recovery of S-ET was achieved in bile, whereas only 30% of the R-enantiomer was recovered via this route of elimination. Urine was a minor route of elimination of ET. It was concluded that the rat may be a suitable pharmacokinetic model for the study of stereoselective pharmacokinetics of ET because, in some aspects, the results closely paralleled those of ET in man.

Volume 18, Issue 4, pp. 471-475, 07/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics