Stereoselective pharmacokinetics and interconversions of flosequinan enantiomers containing chiral sulphoxide in rat.
1. In order to study the pharmacokinetics of flosequinan enantiomers ((+-)-7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) containing chiral sulphur, plasma levels of (+)-(R)- and (-)-(S)-flosequinan (R-FSO and S-FSO) and two metabolites (flosequinan sulphide (FS) and flosequinan sulphone (FSO2)) were measured after oral and i.v. administration of racemic flosequinan (rac-FSO), R-FSO and S-FSO in male rat. 2. The pharmacokinetic parameters of the enantiomers were different after oral and i.v. administration of R-FSO and S-FSO. The plasma clearance of R-FSO was higher than S-FSO. 3. The major metabolites of boh R-FSO and S-FSO was FSO2. A minor metabolite, FS, was also detected in plasma. 4. Interconversions occurred after the oral and i.v. administration of R-FSO and S-FSO. The amount of interconversion from S-FSO and R-FSO was greater than that from R-FSO to S-FSO. The rate of interconversion after oral administration was higher than that after i.v. administration. 5. After i.v. administration of FS, R-FSO and S-FSO were detected in plasma, suggesting that the interconversion occurred via formation of FS. 6. The pharmacokinetic parameters of R-FSO after administration of rac-FSO differed from that after administration of R-FSO, indicating the interaction between each enantiomer.
Kashiyama
E
E
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Todaka
T
T
Odomi
M
M
Tanokura
Y
Y
Johnson
D B
DB
Yokoi
T
T
Kamataki
T
T
Shimizu
T
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011804:Quinolines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013454:Sulfoxides; D014665:Vasodilator Agents / Q000378:metabolism*
D011804:Quinolines; D013454:Sulfoxides; D014665:Vasodilator Agents; C047316:flosequinan