Stereoselective pharmacokinetics and metabolism of flobufen in guinea pigs

✍ Scribed by František Trejtnar; Radim Král; Petr Pávek; Vladimír Wsól

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 105 KB
• Volume: 15
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/chir.10288

✦ Synopsis

Abstract

Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4‐(2′, 4′‐difluorobiphenyl‐4‐yl)‐2‐methyl‐4‐oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac‐flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac‐flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high‐performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R‐ and S‐flobufen. The plasma concentrations of the S‐ and R‐enantiomers differed significantly during the experimental period. The S/R‐enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R‐flobufen was five times higher than S‐flobufen. The other pharmacokinetic parameters (K~e~, T~1/2~, V~SS~/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4‐(2,4‐difluorophenyl)‐phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long‐lasting antiphlogistic and immunomodulatory effects. Chirality 15:724–729, 2003. © 2003 Wiley‐Liss, Inc.