High plasma protein binding as a parameter in the selection of betablockers for lactating women.
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Acebutolol↗
Biomedical subjects
S Urien
Publications and source records attributed to S Urien.
Role of alpha-1 acid glycoprotein, albumin, and nonesterified fatty acids in serum binding of apazone and warfarin.
Altered concentrations of serum proteins and nonesterified fatty acids (NEFAs) often accompany malignant diseases. Free fractions (fu) of apazone and warfarin were measured by equilibrium dialysis in serum samples obtained from 31 patients with cancer and 18 control subjects. Mean fu values of both drugs were significantly higher in the patient group. Multivariate analysis showed albumin, NEFA, and AAG for apazone and albumin, NEFA, and age for warfarin accounted for 60% and 63%, respectively, of interpatient variation in bound/free drug concentration ratios in the group of patients with cancer. The interactions of apazone and warfarin with AAG were further characterized; the more avid site had association constants of 4.5 X 10(5) and 2.3 X 10(5) L/mol, respectively. Finally, it is strongly suggested that when hypoalbuminemia is present and a drug binds to AAG with an affinity constant comparable to or higher than that to albumin, then fu will become dependent on the concentration of AAG.
Adult↗
Diclofenac binding to albumin and lipoproteins in human serum.
The binding of diclofenac to human serum albumin (HSA) and to lipoproteins was studied in vitro by equilibrium dialysis. Binding to HSA is characterized by two classes of sites with one site each (K1 = 5 X 10(5) M-1 and K2 = 0.6 X 10(5) M-1). The binding to lipoproteins was shown to be saturable with a larger number of binding sites and low association constants. The evidence of two specific binding sites on HSA was confirmed by circular dichroism data. In addition, an identification of those sites was performed by displacement of fluorescent probes. The data show that the high affinity site (K1 = 5 X 10(5) M-1) is likely to be shared by benzodiazepines while the second one (K2 = 0.6 X 10(5) M-1) is common with the warfarin site.
Binding Sites↗
Interactions between smectite, a mucus stabilizer, and acidic and basic drugs. In vitro and in vivo studies.
The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and in-vitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.
Absorption↗
The binding of aryl carboxylic acid derivatives to human serum albumin--a structure-activity study.
The binding interactions of some aryl carboxylic acid derivatives have been examined by circular dichroism and fluorescence spectroscopy. With specific probes, we have shown that the seven ligands under study bind primarily to the benzodiazepine site on HSA. Their association constants are in the range of 10(5)-10(6) M-1 as found by spectropolarimetric titration, and appear to be closely related to some chemical features. It is concluded that the binding is enhanced by the lengthening of the carbon chain substituent with a terminating carboxyl moiety and by halogen substitution in the aromatic rings. It is further shown that hydrophilic substitutions such as hydroxyl or ketone groups in the carbon chain substituent will decrease the binding.
Binding Sites↗
Multiple binding of bepridil in human blood.
Using radiolabelled bepridil, equilibrium dialysis experiments and direct ligand-binding studies were conducted to characterize the binding of bepridil to some human serum proteins, and to blood cells and platelets, respectively. Bepridil was bound to serum albumin with K = 26 +/- 1.6 X 10(3) mol-1 X 1, n = 1.07 +/- 0.04; to alpha 1-acid glycoprotein with K = 442 +/- 68 X 10(3) mol-1 X 1, n = 0.90 +/- 0.04; and with a lesser extent to lipoproteins and gamma-globulins. Bepridil, propranolol, quinidine and erythromycin were found to share the same site on alpha 1-acid glycoprotein. The binding of bepridil to both RBC and WBC was nonspecific with the following parameters: NK = 10.55 +/- 0.10 per 5 X 10(6) RBC/mm3 and NK = 0.34 +/- 0.01 per 10(3) WBC/mm3, whereas the binding to platelets was saturable with N = 10.97 +/- 1.06 mumol/l per 108 +/- 10(3) platelets/mm3 and K = 40 +/- 8 X 10(3) mol-1 X 1. The binding parameters were used to simulate the distribution of bepridil between serum proteins, blood cells and platelets over the therapeutic range and showed that serum albumin, alpha 1-acid glycoprotein and RBC were the major binding components.
Bepridil↗
In vitro studies on the distribution of probucol among human plasma lipoproteins.
The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.
Apolipoproteins↗
[Fixation of drugs on plasma proteins].
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Biological Availability↗
Evidence for binding of certain acidic drugs to alpha 1-acid glycoprotein.
The binding of some acidic drugs to alpha 1-AGP was studied by equilibrium dialysis at 37 degrees, pH 7.4. Certain acidic drugs bound to alpha 1-AGP at one binding site with a high affinity. Though the alpha 1-AGP plasma concentration is far lower than the HSA concentration, the association constants of some acidic drugs with alpha 1-AGP are high enough to suggest that binding to alpha 1-AGP will contribute significantly to the total plasma binding of these drugs.
Humans↗
Benoxaprofen: plasma binding and binding interactions with some drugs and endogenous compounds.
The binding of benoxaprofen to human serum albumin (HSA) was investigated by equilibrium dialysis at pH 7.4 and 37 degrees C. As most acidic drugs, almost completely ionized at plasma pH, benoxaprofen was avidly bound to HSA (7.5 x 10(-6) M) with the following parameters: n1 = 3.3 and K1 = 325 x 10(3) M-1; n2 = 16.2 and K2 = 2.1 x 10(3) M-1 At normal HSA plasma concentration in humans benoxaprofen was more than 99.5% bound, either when a pure HSA solution or when a pooled serum was used. Such results were obtained within a wide range of benoxaprofen concentrations and benoxaprofen binding did not significantly differ whatever its concentration might be. The influence of liver failure on benoxaprofen serum binding was investigated in five patients whose bilirubinaemia was from 15 to 28 x 10(-6) M, and the results were compared to those of five normal volunteers. There was no difference between the two groups: 99.30 +/- 0.30% versus 99.62 +/- 0.30%. However, in four other patients whose bilirubinaemia was greater than 130 x 10(-6) M, the binding of benoxaprofen decreased to 98.0 +/- 1.6% (p] less than 0.05). Addition of FFA (palmitic acid, 2000 . 10(-6) M) to H SA (580 x 10(-6) M) involved a slight decrease in HSA binding of benoxaprofen: 99.8 +/- 0.1 versus 99.66 +/- 0.03%. Serum binding of benoxaprofen was not affected by therapeutic levels of tolbutamide, was slightly decreased from 99.7 to 9.2% by furosemide, to 99.4% by CPIB, and to 99.4% by salicylic acid. At the reverse, therapeutic plasma levels of benoxaprofen did not displace warfarin and acenocoumarol, but they displaced CPIB from 90.1 to 86.1%, glibenclamide from 95.2 to 94.2% and phenylbutazone 99.6 to 93.0%.
Anti-Inflammatory Agents↗
Serum protein binding of valproic acid in healthy subjects and in patients with liver disease.
The binding parameters of valproic acid (VPA) to human serum albumin (HSA) were determined by equilibrium dialysis and computed using non-linear regression. However unclassic, it was observed that the binding parameters of VPA varied according to the concentration of the HSA solutions used. At 580 microM HSA, VPA is bound to two classes of binding sites with the association constants K1 = 56000 M(-1) and K2 = 750 M(-1), and their respective numbers of binding sites n1 = 2 and n2 = 5. Free serum fraction of VPA is significantly increased by 500, 1000 and 1500 microM palmitate, 250 microM clofibrate, 320 microM phenylbutazone, or 360 microM salicylate. In any case, the increase of the VPA serum free fraction is highly correlated with the inhibitor concentration. On the other hand, the free serum fraction of warfarin is increased by 600 microM VPA (100 micrograms/ml). In patients with liver disease, the variations of the free serum fraction of VPA are correlated to the albumin and to the bilirubin concentrations. Serum binding of VPA is significantly decreased in the two groups of patients as compared with the control group.
Binding, Competitive↗
Methodological aspects of the evaluation of the binding of drugs to plasma and tissue proteins.
This paper describes the methodological aspects of the evaluation of the binding of drugs to plasma and tissue proteins. The relevance of the procedures employed to certain problems in clinical-pharmacology as well as the role of plasma binding in drug distribution and pharmacokinetics are discussed. The possibly important role of plasma protein binding of some drugs is emphasized. The incidence of plasma binding on drug distribution and pharmacokinetics are developed and the possible incidence of pathological states on drug plasma binding are considered.
Animals↗
[Possible pharmacologic significance of the binding of medication to plasma proteins].
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Blood Proteins↗
Stereoselective binding of tertatolol and of 4-hydroxytertatolol to human plasma proteins.
The binding of racemic tertatolol and 4-hydroxytertatolol and of their enantiomers was compared in alpha 1-acid glycoprotein and albumin solutions. The binding rate of S(-)tertatolol to alpha 1-acid glycoprotein was much greater than that of R(+)tertatolol, the binding of the racemate being intermediate. It was the reverse for the binding to albumin, although the differences were slight. The binding of 4-hydroxytertatolol racemate and enantiomers was very low as compared to the binding of tertatolol, and there were no statistically significant differences in the binding of the 4-hydroxytertatolol enantiomers to either alpha 1-acid glycoprotein or albumin.
Adrenergic beta-Antagonists↗
A re-evaluation of the HSA-piroxicam interaction.
Piroxicam binding to HSA was studied using equilibrium dialysis and fluorescence methods. It was shown that this drug, like its analogs isoxicam and tenoxicam, binds to the apazone locus (site I area) and to a lesser extent to the diazepam site (site II). The piroxicam binding to HSA can be modulated by various specific ligands--apazone, warfarin, diazepam, ibuprofen--and these drug interactions have to be considered not only as potential displacement from the HSA binding sites but also in terms of induced allosteric effects.
Apazone↗
Plasma protein binding and erythrocyte partitioning of nicardipine in vitro.
Using isotope techniques, equilibrium dialysis, and incubation experiments, we characterized the binding of nicardipine to isolated plasma proteins, human serum, blood cells, and platelets. Nicardipine was mainly bound to lipoproteins, orosomucoïd, albumin, and erythrocytes in human blood. Nicardipine, pindolol, and imipramine were found to share the same site on orosomucoïd. The determinants of nicardipine binding to lipoproteins were triglycerides, phospholipids, and cholesterol ester. Nicardipine partitioned into erythrocytes, showing a constant ratio of distribution between the intra- and extracellular compartments. Nicardipine partitioned less to erythrocytes when increasing amounts of binding plasma proteins were present in the extracellular compartment. In human blood, 12 to 18% of total nicardipine was present in erythrocytes. The overall binding of nicardipine in serum varied from 98 to 99.5% and correlated with serum orosomucoïd and serum lipid concentrations.
Blood Proteins↗
Pharmacokinetic modelling of ifosfamide administered by continuous infusion on 5 days at the dose of 6 g/m2.
BACKGROUND: We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity. MATERIAL AND METHODS: We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model. RESULTS: Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume. CONCLUSION: Levy's model is more accurate and takes into account the integration of clearance.
Adolescent↗
Comparison of two dose prediction models for cisplatin.
Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, a limited sampling method was established and validated based on a Bayesian approach taken using the values of assays during a 5-day continuous infusion of cisplatin. Using this method, a dosing model to achieve a target plasma concentration of total platinum (Pt) was evaluated retrospectively; the calculated dose of cisplatin was 95.0 to 104.8% of the actual dose. This model was then studied prospectively and the actual plasma Pt concentration reached at the end of the infusion was 94.9% of the target concentration. A strong correlation was observed between the clearance of Pt and the calculated clearance of creatinine or Cockroft index (p = 1.7 x 10(-11), and this correlation was used to develop another cisplatin dosing model. With this model the actual concentration reached at the end of the infusion was 85.3% of the theoretical concentration. The Bayesian approach gave reliable results for most clinical uses, whereas the creatinine based model has to be improved.
Bayes Theorem↗