Relationships between binding of benzodiazepines to alpha‐1‐acid glycoprotein and human serum albumin and their retention on the protein and octadecylsilane columns
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Abstract:
Correlation between binding parameters of 6 benzodiazepines to free human serum albumin (HSA) and chromatographic retention parameters on the HSA stationary phase (HSA-SP) was better than the similar correlation with alpha-1-acid glycoprotein (AGP). Still better correlation was obtained between binding to both proteins and retention on an octadecylsilane (ODS) column. For 12 benzodiazepines the correlations of the retention parameters on both protein columns with the retention on the ODS column were additionally investigated. In the case of HSA this correlation was good.Keywords:
Human serum albumin
Orosomucoid
Serum Albumin
Retention time
Alpha (finance)
Correlation between binding parameters of 6 benzodiazepines to free human serum albumin (HSA) and chromatographic retention parameters on the HSA stationary phase (HSA-SP) was better than the similar correlation with alpha-1-acid glycoprotein (AGP). Still better correlation was obtained between binding to both proteins and retention on an octadecylsilane (ODS) column. For 12 benzodiazepines the correlations of the retention parameters on both protein columns with the retention on the ODS column were additionally investigated. In the case of HSA this correlation was good.
Human serum albumin
Orosomucoid
Serum Albumin
Retention time
Alpha (finance)
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The binding of thioridazine and some of its psychoactive metabolites to human serum and to human albumin was studied using equilibrium dialysis. A very important binding capacity was found for each of the products tested, but significant differences between binding to human serum and binding to human albumin were observed.
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Human serum albumin
Serum Albumin
Human albumin
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Alpha-1-acid glycoprotein (AGP, also known as AAG or orosomucoid) is an important plasma protein involved in the binding and transport of many drugs, especially basic compounds. AGP has some unique drug-binding properties that differ from those of albumin. For example, the plasma concentration of AGP is relatively low and there is only one drug-binding site in each AGP molecule. Thus, binding to AGP is saturable and displaceable. This could have potential implications for drug-drug interactions or toxicological consequences. Furthermore, AGP is an acute phase protein and the concentration of AGP in plasma can significantly increase in various diseases (such as cancer and inflammatory diseases) or following trauma (burns, surgery). Changes in AGP concentration could potentially alter the free fraction of drugs in plasma or at their target sites and eventually affect their pharmacokinetic disposition and pharmacological action. Given that an increasing number of drugs have been shown to bind preferrentially to AGP, a better understanding of this unique interaction may provide great benefit for drug discovery and development. In this review, we will focus on the effect of altered AGP binding on the pharmacokinetics and pharmacodynamics (PK/PD) of drugs, as well as the species differences in AGP binding.
Orosomucoid
Pharmacodynamics
Free fraction
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Orosomucoid
Human serum albumin
Serum Albumin
Free fraction
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The relative role of lipoproteins, albumin and orosomucoid in the serum binding variation of various drugs was examined by separate removal of these proteins. Lipoproteins were removed from serum by ultracentrifugation, albumin by affinity chromatography and orosomucoid by immunoprecipitation. Removal of the lipoproteins did not affect the serum binding of the acidic (phenytoin) and neutral (digitoxin) drugs tested, nor the basic drugs disopyramide, quinidine or propranolol. A reduction in binding of amitryptyline, nortriptyline, doxepin and desmethyldoxepin was observed. Removal of albumin did, with some exception for nortriptyline, not affect the serum binding of the basic drugs tested. A pronounced reduction in the binding of phenytoin and digitoxin was observed. Removal of orosomucoid did not affect the binding of the acidic and neutral drugs tested. A reduction in the binding of all the basic drugs tested was observed, especially for disopyramide whose binding almost disappeared. Quinidine, propranolol, phenytoin and digitoxin all bound to isolated lipoproteins, but the removal of lipoproteins had no effect on the total serum binding for these drugs. Hence, the use of deficient sera provides valuable information as to the quantitative role of the various proteins in drug binding, whereas studies using purified proteins are often necessary to examine the mechanisms of the drug protein interactions.
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Disopyramide
Digitoxin
Quinidine
Serum Albumin
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Retention time
Gradient elution
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Human serum albumin (HSA) is the major plasma protein with vital functions acting as depot and career for many endogenous (fatty acids, bilirubin, etc.) and exogenous substances (drugs, nutrients, etc.) in the blood. Binding to HSA controls the free, active concentration of the drug and may affect considerably the overall pharmacodynamic and pharmacokinetic profile. Studies on drug - protein binding are important from both theoretical and practical point of view as they allow better understanding of the processes underlying drug disposition and elimination and the effect of several pathological states or co-administered drugs on drug delivery and efficacy. The present review focuses on the current state of drug - HSA binding studies. The major functions and consequences of drug - protein binding are described. The X-ray structure of HSA is discussed focusing on the location and the architecture of the primary drug and fatty acids binding sites. Some of the most commonly used methods for drug - HSA binding assay are presented together with examples for their application. The most extensive studied topics in the area are discussed including quantitative characterization of drug - HSA complexation, identification of the binding sites, stereoselectivity of drug - HSA interactions, and thermodynamic characterization of the binding process. A short section is devoted to in silico prediction of drug - HSA binding as an important step in drug design and development.
Human serum albumin
Serum Albumin
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The interactions between a set of drugs, selected on the basis of reported human serum albumin (HSA) binding levels, and immobilized HSA were investigated using surface plasmon resonance technology. Major HSA binding sites were available after immobilization. The intensity of the signal obtained from the interaction of the drug with the HSA surface was correlated with the reported HSA binding level. Drugs were classified into groups corresponding to high, medium, or low HSA binding based on the injection of the drug at 80 microM concentration. A set of 10 drugs binding to alpha(1)-acid glycoprotein (AGP) was also investigated and correlated with reported AGP binding data. The throughput of the presented assay is 100 compounds/24 h, and the sample consumption is less than 100 microL (8 nmol).
Human serum albumin
Orosomucoid
Serum Albumin
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Alpha-1-acid glycoprotein (AGP, also known as AAG or orosomucoid) is an important plasma protein involved in the binding and transport of many drugs, especially basic compounds. AGP has some unique drug-binding properties that differ from those of albumin. For example, the plasma concentration of AGP is relatively low and there is only one drug-binding site in each AGP molecule. Thus, binding to AGP is saturable and displaceable. This could have potential implications for drug-drug interactions or toxicological consequences. Furthermore, AGP is an acute phase protein and the concentration of AGP in plasma can significantly increase in various diseases (such as cancer and inflammatory diseases) or following trauma (burns, surgery). Changes in AGP concentration could potentially alter the free fraction of drugs in plasma or at their target sites and eventually affect their pharmacokinetic disposition and pharmacological action. Given that an increasing number of drugs have been shown to bind preferrentially to AGP, a better understanding of this unique interaction may provide great benefit for drug discovery and development. In this review, we will focus on the effect of altered AGP binding on the pharmacokinetics and pharmacodynamics (PK/PD) of drugs, as well as the species differences in AGP binding.
Orosomucoid
Pharmacodynamics
Free fraction
Cite
Citations (98)