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Effect of Warfarin on the Metabolism of Phylloquinone (Vitamin K1): Dose—Response Relationships in Man

M. J. Shearer, A. McBurney, A. M. Breckenridge, P. Barkhan
Clinical Science Jun 01, 1977, 52 (6) 621-630; DOI: 10.1042/cs0520621
M. J. Shearer
Department of Haematology, Guy's Hospital, London
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A. McBurney
Department of Haematology, Guy's Hospital, London
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A. M. Breckenridge
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
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P. Barkhan
Department of Haematology, Guy's Hospital, London
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Abstract

1. The dose—response relationship between the oral anticoagulant, warfarin, and its effect on the metabolism of phylloquinone (vitamin K1) has been examined in normal male volunteer subjects.

2. In each study the subject received a single, oral dose of warfarin and, 2 h later, an intravenous injection of [1′,2′-3H2]phylloquinone. Changes in the metabolism of phylloquinone were assessed by the fractionation and chromatographic separation of labelled phylloquinone and its metabolites in plasma and urine samples.

3. Increasing doses of warfarin did not affect the rate of disappearance of injected phylloquinone from the plasma but caused the accumulation of increasing amounts of the metabolite, phylloquinone epoxide.

4. Increasing doses of warfarin were found to decrease the proportion of labelled conjugates excreted in the urine as glucuronides and to block progressively the excretion of the normal aglycones of phylloquinone. At the same time there was a progressive increase in the excretion of at least three abnormal aglycones of phylloquinone.

5. The doses or plasma concentrations of warfarin were related to the increase in phylloquinone epoxide in the plasma and to the decrease in the proportion of normal aglycones of phylloquinone in urine by typical log dose—response curves, which were linear over the therapeutic range.

6. The nature of the metabolites detected suggested that the dose—response curves reflected the progressive inhibition by warfarin of the enzyme, phylloquinone epoxide reductase.

7. The results are consistent with the hypothesis that the pharmacological action of oral anticoagulants is closely linked to their ability to inhibit the cyclic interconversion of vitamin K and vitamin K epoxide.

  • dose—response relationship (drug)
  • phylloquinone reductase
  • phytonadione
  • vitamin K
  • warfarin
  • © 1977 The Biochemical Society and the Medical Research Society
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June 1977

Volume: 52 Issue: 6

Clinical Science: 52 (6)
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Effect of Warfarin on the Metabolism of Phylloquinone (Vitamin K1): Dose—Response Relationships in Man
M. J. Shearer, A. McBurney, A. M. Breckenridge, P. Barkhan
Clinical Science Jun 1977, 52 (6) 621-630; DOI: 10.1042/cs0520621
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Effect of Warfarin on the Metabolism of Phylloquinone (Vitamin K1): Dose—Response Relationships in Man
M. J. Shearer, A. McBurney, A. M. Breckenridge, P. Barkhan
Clinical Science Jun 1977, 52 (6) 621-630; DOI: 10.1042/cs0520621

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Keywords

dose—response relationship (drug)
phylloquinone reductase
phytonadione
vitamin K
warfarin

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