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Stereospecificity of flobufen metabolism in guinea pigs in vitro and in vivo: Phase I of biotransformation
Author(s) -
Kral Radim,
Skalova Lenka,
Szotakova Barbora,
Babu Yogeeta N.,
Wsol Vladimir
Publication year - 2003
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.10298
Subject(s) - microsome , metabolite , stereospecificity , chemistry , biotransformation , in vivo , cytosol , excretion , urine , in vitro , enantiomer , metabolism , s9 fraction , guinea pig , biochemistry , enzyme , stereochemistry , biology , endocrinology , microbiology and biotechnology , catalysis
Flobufen (F) is an original nonsteroidal antiinflammatory drug that exists in two enantiomeric forms. Its biotransformation was investigated in male guinea pigs because of the similarities shown in a preliminary F metabolic study between guinea pig and man. Stereospecificity of the respective enzymes was studied in vitro, using microsomes and cytosol, and in vivo, in urine and feces. Rac ‐F, R‐F, and S‐F served as substrates. The amount of 4‐dihydroflobufen stereoisomers (DHF) and other metabolites (M‐17203 and UM‐2) was determined by chiral HPLC using an R,R‐ULMO column. It was observed that F reductases were distributed differently in microsomes and cytosol. The microsomal fraction showed higher activity and different stereospecificity in rac ‐F, R‐F, and S‐F reduction compared to cytosol. (2R;4S)‐DHF was the principle metabolite in microsomes and (2S;4S)‐DHF was the principle metabolite in cytosol. In vivo experiments revealed the excretion of a main metabolite UM‐2 in addition to other metabolites M‐17203 and DHF stereoisomers. UM‐2 was predominantly excreted after S‐F administration. Stereoselectivity of DHF stereoisomers excretion was different in urine and in feces. The absence of UM‐2 and M‐17203 in microsomes and cytosol and their presence in urine and feces showed that both could arise in some other extrahepatic tissue or cell compartment or that their formation depends on liver cell integrity. Chirality 16:1–9, 2004. © 2003 Wiley‐Liss, Inc.