Stereoselective pharmacokinetics of flobufen in rats

Stereoselectivity of the pharmacokinetics of the nonsteroidal antiinflammat ory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic a cid, was studied in male Wistar rats after intravenous administration. Phar macokinetic parameters and chiral inversion of flobufen enantiomers were st udied after a bolus injection of the racemate and individual enantiomers (5 mg/kg). Determinations of the enantiomers in rat plasma were performed usi ng chiral HPLC (terguride column). After i.v. administration of flobufen ra cemate, plasma levels of R-enantiomer decreased more rapidly. The S/R-enant iomer ratio of AUCs after rac-flobufen was 13.3. The total plasma clearance value of S-flobufen was more than 10-fold lower than R-flobufen. The other pharmacokinetic parameters of the enantiomers were also significantly diff erent. While only traces of R-enantiomer (less than 1%) were detected in ra t plasma after S-flobufen administration, considerable conversion to the S- enantiomer was found after injection of R-flobufen (R-enantiomer AUC/S-enan tiomer AUC = 0.52). The results indicate substantial stereoselectivity in t he disposition of flobufen enantiomers in the rat, which is, at least in pa rt, attributed to chiral bioconversion. Chirality 11:781-786, 1999. (C) 199 9 Wiley-Liss, Inc.