title: Biotransformation of flobufen enantiomers in ruminant hepatocytes and subcellular fractions.
abstract: Flobufen (F), a new antiinflammatory drug, has one chiral and one prochiral center in its structure. Reduction of rac-F, the principal biotransformation pathway, leads to the formation of four diastereoisomers of 4-dihydroflobufen (DHF). F was chosen as a model substrate for interspecies comparison of activity, stereospecificity, and stereoselectivity of biotransformation enzymes in fallow bucks, red deer stags, and roe bucks in vitro. Formation of F metabolites was examined in hepatocyte suspension and in subcellular fractions of liver homogenate. (+)-R-F, (-)-S-F and rac-F were used as substrates. After incubation of substrates, the amounts and ratios of DHF diastereoisomers and F enantiomers were assessed by HPLC, with (R,R)-ULMO and terguride-bonded columns. Considerable interspecies differences in stereoselectivity and stereospecificity of F reductases were found at the cellular and subcellular levels, although these ruminants are closely related. Chiral inversion of F enantiomers to their antipodes was detected in vitro in all ruminants tested, but individual species also differed in the direction and rate of this inversion.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Research Centre LN 00B125, Charles University, Hradec Králové, Czech Republic. SKAOVAL@FAF.CUNI.CZ
authors.forename: L
authors.initials: L
authors.lastname: Skálová
authors.forename: B
authors.initials: B
authors.lastname: Szotáková
authors.forename: J
authors.initials: J
authors.lastname: Lamka
authors.forename: R
authors.initials: R
authors.lastname: Král
authors.forename: I
authors.initials: I
authors.lastname: Vanková
authors.forename: V
authors.initials: V
authors.lastname: Baliharová
authors.forename: V
authors.initials: V
authors.lastname: Wsól
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics*; D002087:Butyrates / Q000737:chemistry* / Q000493:pharmacokinetics*; D003600:Cytosol / Q000378:metabolism; D003670:Deer / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002087:Butyrates; C056474:flobufen