Warfarin: stereochemical aspects of its metabolism in vivo in the rat.
The biotransformation of the R and S isomers of warfarin was investigated in the rat. The formation of 7-hydroxywarfarin was stereoselective for the R enantiomer, while the formation of 4'-hydroxywarfarin was stereoselective for the S enantiomer. The 6-, 8-, and benzylic hydroxylation of both isomers was approximately the same. The reduction of the side chain ketone function of warfarin to the corresponding diastereomeric warfarin alcohols was stereoselective for the S isomer. The reduction also displayed a degree of stereospecificity with S reduction occurring predominantly. The results of the in vivo study agree in many cases with a previous in vitro investigation. However, differences between the in vitro and in vivo studies do exist and suggest that secondary stereoselective biotransformation routes occur in vivo and that the microsomal and soluble enzymes employed in the in vitro study may have been disrupted during isolation. Large amounts of polar labile conjugates of R and S warfarin, and metabolites were found in the urine. The 4-hydroxyl group of the coumarin ring appears to be the position of conjugation and this process appears to be regio and stereoselective.
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D005243:Feces / Q000032:analysis; D066298:In Vitro Techniques; D008099:Liver / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000032:analysis / Q000378:metabolism* / Q000652:urine
D014859:Warfarin