Stereoselective S-oxidation and reduction of flosequinan in rat.
1. The stereoselective S-oxidation and reduction pathways of flosequinan [(+/-)-7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone] in rat were investigated in vitro. 2. Cytosol from both the liver and kidney catalysed the reduction of R(+)-flosequinan (R-FSO) and S(-)-flosequinan (S-FSO) to flosequinan sulphide (FS, 7-fluoro-1-methyl-3-methylthio-4-quinolone). Flosequinan sulphone (FSO2, 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone) was not reduced to R-FSO or S-FSO. 3. Liver microsomes catalysed four different S-oxidation pathways in the presence of NADPH, namely oxidation of FS to R-FSO and S-FSO and from R-FSO and S-FSO to FSO2. The formation of R-FSO and S-FSO from FS each exhibited a biphasic kinetic pattern, indicating that at least two distinct enzymes were involved. The pathway from FS to R-FSO appeared mainly catalysed by flavin-containing monooxygenases (FMO). 4. S-oxidation of FS to R-FSO was more rapid than that of FS to S-FSO. S-oxidation of FS to either R-FSO or S-FSO in liver microsomes was more rapid than that of either R-FSO or S-FSO to FSO2. 5. Microsomes from both the kidney and lung catalysed the stereoselective S-oxidation of FS to R-FSO, and FMO was likely to have participated in these reactions.
Kashiyama
E
E
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. e_kashiyama@research.otsuka.co.jp
Yokoi
T
T
Odomi
M
M
Kamataki
T
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006035:Glycyrrhiza; D006358:Hot Temperature; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000276:immunology / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D029596:Paeonia; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000737:chemistry / Q000378:metabolism*
D000906:Antibodies; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D011804:Quinolines; D014665:Vasodilator Agents; C038462:shakuyaku-kanzoh-toh; D009249:NADP; C047316:flosequinan; D010088:Oxidoreductases; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase