Stereoselective pharmacokinetics of flobufen in rats.
Stereoselectivity of the pharmacokinetics of the nonsteroidal anti-inflammatory drug flobufen, 4-(2', 4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, was studied in male Wistar rats after intravenous administration. Pharmacokinetic parameters and chiral inversion of flobufen enantiomers were studied after a bolus injection of the racemate and individual enantiomers (5 mg/kg). Determinations of the enantiomers in rat plasma were performed using chiral HPLC (terguride column). After i.v. administration of flobufen racemate, plasma levels of R-enantiomer decreased more rapidly. The S-/R-enantiomer 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 different. While only traces of R-enantiomer (less than 1%) were detected in rat plasma after S-flobufen administration, considerable conversion to the S-enantiomer was found after injection of R-flobufen (R-enantiomer AUC/S-enantiomer AUC = 0.52). The results indicate substantial stereoselectivity in the disposition of flobufen enantiomers in the rat, which is, at least in part, attributed to chiral bioconversion.
Trejtnar
F
F
Charles University, Prague, Faculty of Pharmacy, Department of Pharmacology and Toxicology, Department of Biochemical Sciences, Hradec Kralove, Czech Republic. tretfr@faf.cuni.cz
Wsol
V
V
Szotakova
B
B
Skalova
L
L
Pavek
P
P
Kuchar
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002087:Butyrates / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002087:Butyrates; C056474:flobufen