title: Chiral aspects of metabolism of antiinflammatory drug flobufen in human hepatocytes.
abstract: The metabolism of the nonsteroidal antiinflammatory drug flobufen, 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, was studied in primary cultures of human hepatocytes prepared by two-step collagenase perfusion of livers from four donors. Racemic flobufen or its individual enantiomers, R-(+)- and S-(-)-flobufen were used as substrates. Aliquots of culture medium were collected during 24-h incubation. The time-dependent disappearance of flobufen enantiomers and the formation of metabolites (stereoisomers of dihydroflobufen (DHF)) in hepatocytes were measured by chiral HPLC. The reduction of flobufen in human hepatocytes was stereoselective ((+)-R-flobufen was preferentially metabolized) and stereospecific ((2R;4S)-DHF and (2S;4S)-DHF stereoisomers were mostly formed). Although the structure of flobufen is different from the profens (2-arylpropionates), flobufen undergoes chiral inversion in human hepatocytes. The inversion of R-(+)-flobufen to S-(-)-flobufen predominates. The individual DHF stereoisomers were incubated in hepatocyte cultures and their biotransformation studied. The unidirectional chiral inversion of (2S;4S)-DHF to (2R;4S)-DHF and (2R;4R)-DHF to (2S;4R)-DHF was observed. Stereoselective oxidation of the DHFs to flobufen was also detected. Thus, flobufen metabolism in primary cultures of human hepatocytes is much more complicated (via chiral inversion and DHF re-oxidation) than was presumed from a preliminary achiral point of view.
authors.affiliation: Department of Biochemical Sciences, Research Centre LN00B125, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic. skaloval@faf.cuni.cz
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
authors.forename: Radim
authors.initials: R
authors.lastname: Král
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
authors.forename: Yogeeta N
authors.initials: YN
authors.lastname: Babú
authors.forename: Lydiane
authors.initials: L
authors.lastname: Pichard-Garcia
authors.forename: Vladimír
authors.initials: V
authors.lastname: Wsól
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism*; D001711:Biotransformation; D002087:Butyrates / Q000737:chemistry* / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002087:Butyrates; C056474:flobufen