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. 1974 Jun;53(6):1607–1617. doi: 10.1172/JCI107711

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Richard J Lewis 1,2,3,4, William F Trager 1,2,3,4, Kenneth K Chan 1,2,3,4, A Breckenridge 1,2,3,4, M Orme 1,2,3,4, Malcolm Roland 1,2,3,4, William Schary 1,2,3,4
PMCID: PMC302656  PMID: 4830225

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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