title: Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone.
abstract: An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004347:Drug Interactions; D006801:Humans; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D010653:Phenylbutazone / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding; D011517:Prothrombin Time; D013237:Stereoisomerism; D014859:Warfarin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine / Q000031:analogs & derivatives
chemical_list: D014859:Warfarin; D010653:Phenylbutazone; C008091:6-hydroxywarfarin