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Research Article Free access | 10.1172/JCI107711

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Richard J. Lewis, 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

Find articles by Lewis, R. in: 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 Trager, W. in: 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 Chan, K. in: 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: 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: 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 Roland, M. in: 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 Schary, W. in: PubMed | Google Scholar

Published June 1, 1974 - More info

Published in Volume 53, Issue 6 on June 1, 1974
J Clin Invest. 1974;53(6):1607–1617. https://doi.org/10.1172/JCI107711.
© 1974 The American Society for Clinical Investigation
Published June 1, 1974 - Version history
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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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Referenced in 1 policy sources
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32 readers on Mendeley
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