Studies on the 4-Hydroxycoumarins. XVII.<sup>1a</sup> The Resolution and Absolute Configuration of Warfarin<sup>1b</sup>

West, Bruce D.; Preis, Seymour; Schroeder, Collin H.; Link, Karl Paul

doi:10.1021/ja01473a020

Cited by 158 publications

(53 citation statements)

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“…There are two isomeric forms, the (R) (+) -warfarin (R warfarin) and the (S) (-) -warfarin (S warfarin) isomers (1). The clinically available formulation is a racemate, a mixture of equal parts of each isomer.…”

Section: Introductionmentioning

confidence: 99%

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Lewis¹,

Trager²,

Chan³

et al. 1974

J. Clin. Invest.

274

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A B S T R A C T 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 stereospecifically, 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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Section: Introductionmentioning

confidence: 99%

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Lewis¹,

Trager²,

Chan³

et al. 1974

J. Clin. Invest.

274

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“…The warfarin which was available for these studies was the racemic mixture of R and S isomers (4). Acetonyl reduction produced a second asymmetric carbon atom (Fig.…”

Section: Resultsmentioning

confidence: 99%

Warfarin metabolism in man: identification of metabolites in urine

Lewis¹,

Trager²

1970

J. Clin. Invest.

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A B S T R A C T After administration of the coumarin anticoagulant racemic warfarin to normal humans, seven fluorescent compounds were chromatographically separated from extracts of their urine. Four of these were identified using mass spectrometry, thin-layer chromatography, and ultraviolet absorption spectroscopy. One metabolic pathway, reduction of the acetonyl side chain of warfarin, resulted in the formation of a second asymmetric carbon atom, and two diastereoisomer alcohols were identified. These warfarin alcohols are structurally similar to pharmacologically active coumarin derivatives. They have not been reported in animal studies. In addition, 6-and 7-hydroxywarfarin were identified. These are the first studies to document the metabolic fate of warfarin in the normal human.

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“…Boc-L-Phe was purchased from Peptide Institute (Osaka, Japan . Optically pure warfarin was prepared from racemic warfarin, using a fractional crystallization method [16].…”

Section: Methodsmentioning

confidence: 99%

Preparation and characterization of poly(l-phenylalanine) chiral stationary phases with varying peptide length

Ohyama¹,

Oyamada²,

Kishikawa³

et al. 2008

Journal of Chromatography A

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Three new chiral stationary phases with different lengths of L-phenylalanine peptide were prepared by solid-phase synthesis with Boc-L-phenylalanine on silica. The effect of phenylalanine peptide length on enantioselectivity was studied. The best separation of R/S-warfarin was achieved by the chiral stationary phase with intermediate peptide length. These stationary phases were found to exist mainly in -helical conformation by using FT-IR spectra. The end-capping reagents for the N-terminus of the peptide were also evaluated.3

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Studies on the 4-Hydroxycoumarins. XVII.^1a The Resolution and Absolute Configuration of Warfarin^1b

Cited by 158 publications

References 1 publication

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin metabolism in man: identification of metabolites in urine

Preparation and characterization of poly(l-phenylalanine) chiral stationary phases with varying peptide length

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Studies on the 4-Hydroxycoumarins. XVII.1a The Resolution and Absolute Configuration of Warfarin1b

Cited by 158 publications

References 1 publication

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin metabolism in man: identification of metabolites in urine

Preparation and characterization of poly(l-phenylalanine) chiral stationary phases with varying peptide length

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Studies on the 4-Hydroxycoumarins. XVII.^1a The Resolution and Absolute Configuration of Warfarin^1b