Stereospecificity and stereoselectivity of flobufen metabolic profile in male rats in vitro and in vivo: phase I of biotransformation
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
11746815
DOI
10.1002/chir.10005
PII: 10.1002/chir.10005
Knihovny.cz E-zdroje
- MeSH
- antiflogistika nesteroidní aplikace a dávkování chemie farmakokinetika MeSH
- biotransformace MeSH
- butyráty aplikace a dávkování chemie farmakokinetika MeSH
- cytosol metabolismus MeSH
- hepatocyty metabolismus MeSH
- jaterní mikrozomy metabolismus MeSH
- krysa rodu Rattus MeSH
- molekulární struktura MeSH
- potkani Wistar MeSH
- stereoizomerie MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika nesteroidní MeSH
- butyráty MeSH
- flobufen MeSH Prohlížeč
Flobufen (F) is the original nonsteroidal antiinflammatory drug (NSAID) containing two enantiomers. The aim of this investigation was to elucidate the biotransformation pathway of F at chiral level in phase I of biotransformation. Stereoselectivity and stereospecificity of the respective enzymes were studied in male rats in vitro (microsomal and cytosolic fractions, hepatocytes suspension) and in vivo. The rac-F, (+)-R-F and (-)-S-F were used as substrates. Amounts of F enantiomers, 4-dihydroflobufen diastereoisomers (DHF) and other metabolites (M-17203, UM) were determined with a chiral HPLC method in two chromatographic runs on R,R-ULMO and allyl-terguride bonded columns. Stereoselective biotransformation of the two enantiomers of F was observed at all tested levels and significant bidirectional chiral inversion of enantiomers of F was observed in hepatocytes. Mean enantiomeric ratios of F concentrations (S-/R-), after rac-F incubations, ranging from 1.09 in cytosolic fraction to 18.23 in hepatocytes. Stereospecificity of the respective F reductases was also observed. (2R;4S)-DHF and (2S;4S)-DHF are the principal metabolites of F in microsomes and hepatocytes. Neither DHF diastereoisomers nor M-17203 were found in cytosolic fraction. Only the nonchiral metabolite, M-17203, was found in all urine and feces samples after oral administration of F.
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