Stereoselective pharmacokinetics of flobufen in rats

• Published in: Chirality (New York, N.Y.) N.Y.), 1999, Vol.11 (10), p.781-786
• Main Authors: Trejtnar, Frantisek, Wsol, Vladimir, Szotakova, Barbora, Skalova, Lenka, Pavek, Petr, Kuchar, Miroslav
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; anti-inflammatory drugs; Area Under Curve; Butyrates - blood; Butyrates - chemistry; Butyrates - pharmacokinetics; chiral inversion; Chromatography, High Pressure Liquid; enantioselective disposition; enantioselectivity; Male; phenylbutyrates; Rats; Rats, Wistar; Stereoisomerism
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/(SICI)1520-636X(1999)11:10<781::AID-CHIR7>3.0.CO;2-9

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. Chirality 11:781–786, 1999. © 1999 Wiley‐Liss, Inc.