Chiral inversion of drug: role of intestinal bacteria in the stereoselective sulphoxide reduction of flosequinan.
Chiral inversion at a sulphoxide position of flosequinan enantiomers [(+/-)-7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone] occurred in conventional rats but not in either germ-free rats or rats treated with antibiotics after an oral administration of each enantiomer. Thus, it was postulated that the chiral inversion occurred by mechanisms mediated by intestinal bacteria. The intestinal content isolated from conventional rats reduced R(+)- and S(-)-flosequinan to produce the sulphide, while intestinal content from rats treated with antibiotics did not reduce the drug. Several strains of facultative anaerobes possessed a high flosequinan reducing activity. Escherichia coli, Klebsiella oxytoca and Klebsiella pneumoniae reduced R(+)-flosequinan to the sulphide stereoselectively. On the other hand, Enterobacter aerogenes and Micrococcus agilis exclusively reduced S(-)-flosequinan. The sulphide, which could be produced by intestinal bacteria from R(+)- and S(-)-flosequinan, was readily absorbed upon an oral administration to rats, and was oxidized fairly rapidly to R(+)- and S(-)-flosequinan and further to the sulphone form. Based on these data, it has been confirmed that chiral inversion at the sulphoxide position of flosequinan enantiomers occur via stereoselective reduction of sulphoxide by intestinal bacteria to form the sulphide, followed by oxidation of the sulphide in the body to produce R(+)- and S(-)-flosequinan.
Kashiyama
E
E
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yokoi
T
T
Todaka
T
T
Odomi
M
M
Kamataki
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001419:Bacteria / Q000201:enzymology*; D005856:Germ-Free Life; D007422:Intestines / Q000382:microbiology*; D008297:Male; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011804:Quinolines / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013440:Sulfides / Q000378:metabolism; D013450:Sulfones / Q000378:metabolism; D013454:Sulfoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D011804:Quinolines; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D014665:Vasodilator Agents; C047316:flosequinan; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C030542:sulfoxide reductase