Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE (original) (raw)
Research Article Free access | 10.1172/JCI107711
William F. Trager, Kenneth K. Chan, A. Breckenridge, M. Orme, Malcolm Roland, and William Schary
Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
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Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
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Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
Find articles by Chan, K. in:[JCI](/search/results?q=author.first%5Fname%3A%22Kenneth K.%22+author.last%5Fname%3A%22Chan%22&search%5Ftype=advanced) |PubMed |Google Scholar
Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
Find articles by Breckenridge, A. in:JCI |PubMed |Google Scholar
Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
Find articles by Orme, M. in:JCI |PubMed |Google Scholar
Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
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Veterans Administration Hospital, the Department of Medicine, School of Medicine, San Francisco, California
Department of Pharmacy, School of Pharmacy of the University of California, San Francisco, California
University of Washington, Seattle, Washington
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London
Find articles by Schary, W. in:JCI |PubMed |Google Scholar
Published June 1, 1974 -More info
Published June 1, 1974 -Version history
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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