The effect of various drugs on the binding of warfarin-14C to human albumin

Solomon, Harvey M.; Schrogie, John J.

doi:10.1016/0006-2952(67)90153-0

Cited by 110 publications

(27 citation statements)

References 10 publications

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“…It is generally assumed that only the free drug is liable to metabolism. In in vitro systems, phenylbutazone interferes with the binding of many drugs to albumin, and markedly increases the concentration of free warfarin (34). These data supported the suggestion that phenylbutazone augmented warfarin anticoagulation by a displacement mechanism (35).…”

supporting

confidence: 67%

“…We have previously indicated that the (R,S) and (S,S) warfarin alcohols possess some, but only limited anticoagulant activity (27). The (34); whereas, our limited data, when samples were obtained in vivo, suggested that the levels of free warfarin were much lower: only 1 % of the drug was in the free form after phenylbutazone. Second, if displacement from albumin is the sole mechanism of a drug interaction, it would seem logical to expect that the displacement in vitro be manifest also by more rapid metabolism and elimination in vivo.…”

mentioning

confidence: 68%

“…However, confirmation by accelerated plasma clearance in vivo is not invariably made. For example, clofibrate produced significant displacement of warfarin from albumin in vitro (34), but the plasma clearance of warfarin is unchanged after clofibrate (37). Similarly, there is no change in the clearance of (racemic) warfarin after phenylbutazone.…”

mentioning

confidence: 99%

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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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supporting

confidence: 67%

mentioning

confidence: 68%

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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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“…Phenylbutazone however, unable to occupy the primary site, would bind at the secondary site, and this in turn might result in structural changes at the primary site, thus enhancing binding of additional indomethacin molecules. This sort of noncompetitive interaction has been discussed by Sellars and KochWeser (20), Thorp (24) and Solomon and Schrogie (22).…”

Section: Discussionmentioning

confidence: 75%

Protein Binding of Indomethacin: Binding of Indomethacin to Human Plasma Albumin and its Displacement from Binding by Ibuprofen, Phenylbutazone and Salicylate, <i>in vitro</i>

Mason

McQueen²

1974

Pharmacology

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The reversible binding of indomethacin to human plasmaprotein and the manner in which this may be modified by ibuprofen, phenylbutazone and salicylate was studied by ultrafiltration at 37 °C and pH 7.4. Indomethacin is much more highly bound than has previously been considered. The affinity constant for the single primary binding site is 3 x 10⁵ l/mol and for the seven secondary binding sites 1.4 x 10⁴ l/mol. The protein binding of indomethacin is increased by the presence of phenylbutazone and decreased by the presence of ibuprofen and salicylate. Salicylate in vitro, at concentrations observed clinically, significantly decreases the protein binding of indomethacin.

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“…64). Several other drugs can displace warfarin from its binding to this single high affinity binding site (32,60,61). The pharmacokinetic and pharmacodynamic significance of the serum albumin binding of coumarin anticoagulants and of displacement reactions is well known (3,29).…”

Section: Warfarinmentioning

confidence: 99%

Human Serum Albumin as a ‘Silent Receptor’ for Drugs and Endogenous Substances

Müller

Wollert²

1979

Pharmacology

173

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Most drugs are bound to human serum albumin (HSA) via a few high affinity binding sites and several sites of much lower affinity. There is now increasing evidence that the actual number of high affinity drug-binding sites of HSA is rather small. Thus, each of these binding sites binds several drugs of very different chemical and pharmacological properties with relative high affinity. On the other hand these drug-binding sites can in some cases be very specific and even stereoselective, as demonstrated by the stereospecific binding of drugs to some of these binding sites. The discrepancy between both observations can be explained by the conformational adaptability of the HSA-binding sites.

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The effect of various drugs on the binding of warfarin-14C to human albumin

Cited by 110 publications

References 10 publications

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Protein Binding of Indomethacin: Binding of Indomethacin to Human Plasma Albumin and its Displacement from Binding by Ibuprofen, Phenylbutazone and Salicylate, <i>in vitro</i>

Human Serum Albumin as a ‘Silent Receptor’ for Drugs and Endogenous Substances

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The effect of various drugs on the binding of warfarin-14C to human albumin

Cited by 110 publications

References 10 publications

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

Protein Binding of Indomethacin: Binding of Indomethacin to Human Plasma Albumin and its Displacement from Binding by Ibuprofen, Phenylbutazone and Salicylate, <i>in vitro</i>

Human Serum Albumin as a &lsquo;Silent Receptor&rsquo; for Drugs and Endogenous Substances

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Human Serum Albumin as a ‘Silent Receptor’ for Drugs and Endogenous Substances