Warfarin. Sterochemical aspects of its metabolism and the interaction with phenylbutazone

Abstract

An examination of the metabolic fate of the R and 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 was 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 hr in one subject and from 2.3 to 1.6% per hr in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per hr and from 0.9 to 1.6% per hr 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 5 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.