Difficulties in Applying the Scatchard Model of Ligand Binding to Proteins—Proposal of New Mathematical Tools—Application to Salicylates

Monot, C.; Netter, Patrick; Stalars, M. C.; Martin, Jean‐Charles; Royer, R; Gaucher, A

doi:10.1002/jps.2600720109

Cited by 15 publications

(9 citation statements)

References 17 publications

(6 reference statements)

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“…Their parameter values probably differed from ours because of the multiplicity of solutions obtained in optimisation of a model with four parameters such as the Scatchard model. 28 Our results show that it is stereoselective at HSA concentrations of 20 and 40 g/liter: (R)-ketoprofen bound more strongly than its optical antipode. In the gel filtration study of Rendic et al, the stereoselectivity observed in HSA at 1 gfiter had disappeared at 10 gfiter.…”

Section: Ketoprofen Protein Bindingmentioning

confidence: 88%

Stereoselective protein binding of ketoprofen: Effect of albumin concentration and of the biological system

Dubois

Lapicque

Abiteboul³

et al. 1993

Chirality

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Equilibrium dialysis was used to study in vitro the enantioselective binding of R, S, and racemic ketoprofen at physiological pH and temperature in human serum albumin (HSA) (1, 20, and 40 g/liter) and in plasma. The binding of enantiomers in a racemic mixture was studied to see the effect of each isomer on the other's interaction with the protein. The free fractions were determined by high-performance liquid chromatography. The binding of ketoprofen enantiomers to albumin was enantioselective, depending on both drug and protein concentrations. Enantioselectivity was observed in plasma too but was the opposite of that in HSA at 40 g/liter. The percentage of each isomer unbound was higher in the racemic mixture than with the isomer alone. The displacement of probes specific for HSA sites I and II, studied by spectrofluorimetry, suggests that all three preparations of ketoprofen are bound mainly to site I and secondarily to site II.

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Section: Ketoprofen Protein Bindingmentioning

confidence: 88%

Stereoselective protein binding of ketoprofen: Effect of albumin concentration and of the biological system

Dubois

Lapicque

Abiteboul³

et al. 1993

Chirality

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“…In the present study in vitro, we have investigated a range of salicylate concentrations from 50 j.l.g/ml (312 umol/l) to 2000 j.l.g/ml (12 500 umol/ At / albumin 6 I), i.e. from very low, non-therapeutic concentrations up to concentrations much higher even than those encountered in cases of massive intoxication.…”

Section: Discussionmentioning

confidence: 99%

“…These are due to the over-large number of parameters to be identified given the usual amount and precision of experimental data (5). We have shown that even with only two classes of sites there are in practice very diverse combinations of the four parameters (number of sites and affinity of each class) that can yield the same curve of bound fraction as a function of the total concentration of the substance (6). For example, the values of bound fraction corresponding to the two combinations:…”

Section: B Experimental Methodsmentioning

confidence: 97%

Decrease of in vitro serum protein binding of salicylate in rheumatoid arthritis

Netter

Monot

Stalars

et al. 1984

European Journal of Drug Metabolism and Pharmacokinetics

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Free and bound fractions of salicylates were separated by equilibrium dialysis and measured by spectrofluorimetry in 27 patients with rheumatoid arthritis and in 16 controls. The results showed that in patients with rheumatoid arthritis, the binding of salicylate to proteins decreased in an overproportional manner with the decrease of serum albumin concentrations. This phenomenon was linked with the severity of the inflammatory syndrome. The saturation binding capacity per unit of protein concentration was lower in the patients suffering from active forms of the condition, a finding which suggests that the changes observed are not due only to quantitative changes in the serum albumins. This study confirms the importance of determining free salicylate concentrations in the treatment of patients with inflammatory diseases.

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“…The plasma proteins to which bumetanide binds were not identified in the present study. However, it was assumed that the drug binds methods for determining protein binding pa rameters, the efficiency with which this model represents reality has been questioned because this assumption may be difficult to substantiate [19][20][21], In their evaluation of bumetanide protein binding, Robertson and Karp [14] used a stoichiometric model to describe binding parameters. The underlying assumptions of this model are different from those of the methof of Rosenthal [11], and consequently, these investigators reported data regarding a single class of binding sites.…”

Section: Discussionmentioning

confidence: 99%

Protein Binding Characteristics of Bumetanide

1989

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The association constants (k) and binding capacities (np) of bumetanide were determined in pooled venous blood obtained from adults, venous cord blood of healthy full-term infants, and critically ill neonates using ultrafiltration. Bumetanide was highly bound to plasma proteins (approximately 97%) in all three populations studied. Two classes of binding sites were identified, a high-affinity, low-capacity site with k and np in the order of 10^3 M^-1 and 10^-3 M, respectively, and a low-affinity, high-capacity site with k and np in the order of 10^2 M^-1 and 10^-2 M, respectively. Binding capacities were similar between the three groups studied and were larger than the ‘presumed’ therapeutic concentration following intravenous administration of the drug, which is on the order of 10^-6 M (≤ 0.5 μg/ml).

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Difficulties in Applying the Scatchard Model of Ligand Binding to Proteins—Proposal of New Mathematical Tools—Application to Salicylates

Cited by 15 publications

References 17 publications

Stereoselective protein binding of ketoprofen: Effect of albumin concentration and of the biological system

Stereoselective protein binding of ketoprofen: Effect of albumin concentration and of the biological system

Decrease of in vitro serum protein binding of salicylate in rheumatoid arthritis

Protein Binding Characteristics of Bumetanide

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