Potentiation of Anticoagulant Effect of Warfarin by Phenylbutazone

Aggeler, Paul M.; O’Reilly, Robert A.; Leong, Lois S.; Kowitz, Patricia E.

doi:10.1056/nejm196703022760904

Cited by 222 publications

(52 citation statements)

References 13 publications

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“…The concentration of free warfarin anion in equilibrium with bound anion was determined by measuring the drug concentration outside the dialysis bag. The method used for determining warfarin content (3) will detect concentrations as low as 5 Amoles/liter and has an error of 2%. The amount of albumin-bound warfarin was determined by subtracting the free and bag-bound warfarin from the amount added initially.…”

Section: Warfarin Sodiummentioning

confidence: 99%

“…These were obtained as a white crystalline powder and diluted in buffer without any further purification.s All four metabolites at the concentrations studied (6-100 Amoles/ liter) were insoluble at pH 7.4, but were readily soluble at pH 10.0. The competitive equilibrium dialysis experiments with 7-hydroxywarfarin, nonradioactive warfarin sodium, and warfarin-'4C were performed as described previously (5 …”

Section: Metabolitesmentioning

confidence: 99%

“…For each compound studied v, and v/A and their standard errors at every concentration used were calculated.5 A 5 In our previous study (1) an arithmetic error occurred and all values of i and v/A were low by a factor of 2.5 because in the calculation of v, the albumin molarity was calculated incorrectly on a volume of 25 ml, the total volume regression line was calculated for each set of data by the method of least squares, and kn (equal to the first anion bound or k1) and n were determined by extrapolation as in the previous study (1). The values of v/A plotted against v give a straight line when all the binding sites are independent and equivalent.…”

Section: Calculationsmentioning

confidence: 99%

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Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin

O’Reilly¹

1969

J. Clin. Invest.

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A B S T R A C T The interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin was studied by equilibrium dialysis. A 20-fold variation of buffer ionic strength (0.017-0.340) caused no significant change in the warfarin association constant. But the binding strength rose significantly as the pH was increased from 6.0 to 9.0 and then declined at pH 10.0. The 6-, 7-, and 8-hydroxywarfarin metabolites showed a 7-to 23-fold reduction in binding strength at pH 10.0. These data indicate that the molecular basis of the interaction is nonelectrostatic and that the introduction of polar hydroxyl groups on the coumarin nucleus by metabolism reduces its hydrophobic binding surface. The interaction was markedly exothermic and showed a positive entropy (increased molecular disorder), which suggests cooperative hydrogen and hydrophobic bonding as the molecular basis for the binding of warfarin to albumin.The marked albumin binding and nonpolar character of warfarin explains the respective absence and presence of the unchanged drug in urine and plasma of warfarintreated patients, while the more polar character and lesser albumin binding of the metabolites probably determines their absence in plasma and presence in urine. The relatively marked binding to albumin of the 4'-hy- INTRODUCTIONIn previous studies of the interaction of the coumarin anticoagulant warfarin sodium and human plasma albumin, the drug was strongly bound to plasma albumin when analyzed by equilibrium dialysis (1). While the strength of the interaction was studied as a function of temperature, no experiments were performed at different levels of buffer pH and ionic strength. Such experiments were performed in the present study which together with the thermodynamic data allowed us to analyze the molecular basis of the warfarin-albumin interaction.Countercurrent distribution analysis of plasma of patients receiving clinical doses of warfarin shows essentially only the unchanged drug and similar analysis of urine reveals only hydroxylated metabolites of warfarin (2, 3). To determine if the absence of the metabolites in plasma and the absence of unchanged drug in the urine could be correlated with albumin binding, we also studied the four known metabolites by equilibrium dialysis. Based on these data, a hypothesis is presented for the pharmacodynamics of warfarin in man. METHODS Warfarin sodiumMaterial. The equilibrium dialysis technique, the crystalline human albumin and warfarin sodium, the preparation of the cellophane bags, the experimental techniques employed, the measurement of free and bound drug, and the determination of the standard free energy change were exactly as described previously (1). The low concentrations of warfarin sodium were varied over a 16-fold range (6-100 ,moles/ liter), which evaluates mainly the association constant of the first warfarin anion bound (k1). The concentration of The Journal of Clinical Investigation Volume 48 1969 193 albumin used in all experiments was 0.4% (57.9 /hM/liter). The e...

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Section: Warfarin Sodiummentioning

confidence: 99%

Section: Metabolitesmentioning

confidence: 99%

Section: Calculationsmentioning

confidence: 99%

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Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin

O’Reilly¹

1969

J. Clin. Invest.

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“…In the in vivo study of the competitive effect, ANTON et al 16) showed that the serum levels of sulfaethylthiadiazole (SET) in rats were reduced by the simultaneous administration of sulfinpyrazone (SPZ), and that tissue levels of SET increased.…”

Section: Discussionmentioning

confidence: 99%

Studies on protein binding of antibiotics. I. Effect of cefazolin on protein binding and pharmacokinetics of cefoperazone.

et al. 1980

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“…There are also instances of untoward reactions occurring clinically in which displacement seems likely to have played a significant part. Thus the anticoagulant activity of warfarin is increased dangerously by the concurrent use of phenylbutazone (Eisen, 1964; Aggeler, O'Reilly, Leong & Kowitz, 1967). Sulphonamides enhance the hypoglycaemic action of tolbutamide (Christensen, Hansen & Kristensen, 1963 ;Biittner & Portwich, 1967).…”

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confidence: 99%

Displacement from protein binding of sulphormethoxine by phenylbutazone using in vivo dialysis in rats

McQueen¹

1969

British J Pharmacology

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Displacement of the ultra‐long‐acting sulphonamide sulphormethoxine from binding to serum proteins by phenylbutazone has been demonstrated by in vivo dialysis in rats. The technique used involved the introduction of dialysis sacs into the peritoneal cavity. The regression line relating free to total sulphormethoxine was significantly displaced after addition of phenylbutazone to the regime although the mean level of free drug was not significantly raised. No significant effect was observed on the proportion of phenylbutazone in the free form. The range of concentrations employed corresponded to that encountered clinically. In vitro experiments with comparable concentrations of both drugs confirmed displacement of sulphormethoxine by phenylbutazone. Insignificant displacement of phenylbutazone from binding occurred. These experiments indicated the relationships between the relative affinities of sulphormethoxine and phenylbutazone for serum proteins and the extent to which mutual displacement from binding occurred.

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Potentiation of Anticoagulant Effect of Warfarin by Phenylbutazone

Cited by 222 publications

References 13 publications

Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin

Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin

Studies on protein binding of antibiotics. I. Effect of cefazolin on protein binding and pharmacokinetics of cefoperazone.

Displacement from protein binding of sulphormethoxine by phenylbutazone using in vivo dialysis in rats

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