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 investiga ted in vitro. 2. Cytosol from both the liver and kidney catalysed the reduction of R(+)-f losequinan (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-methyl-sulphonyl-4-quinolone) was not reduced to R-FSO or S-FSO. 3. Liver microsomes catalysed four different S-oxidation pathways in the pr esence of NADPH, namely oxidation of FS to R-FSO and S-FSO and from R-FSO a nd 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 we re involved. The pathway from FS to R-FSO appeared mainly catalysed by flav in-containing monooxygenases (FMO). 4. S-oxidation of FS to R-FSO was more rapid than that of FS to S-FSO. S-ox idation of FS to either R-FSO or S-FSO in liver microsomes was more rapid t han 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.