engleski

Determination of human alpha-1-acid glycoprotein- drug binding constants using microscale thermophoresis

After the drug is administrated to the blood stream, it usually binds to certain plasma proteins. Alpha-1-acid glycoprotein (AGP) is an important plasma protein involved in the binding and transport of many basic and neutral drugs. The extent of this association at equilibrium determines the concentration of unbound drug. Only the free fraction of the drug (unbound drug) is available for active uptake or diffusion into the surrounding tissue according to the “free drug principle”. Due to their high concentration, the plasma proteins control the free drug concentration, thus influencing the drug potency in vivo.[1] Clinically, this buffering effect should be considered when adjusting the dosage of a drug as well as in assessing the toxicity of the administered drug which is often complicated by changes in patient’s protein-binding capacity.[2] For that reason, data obtained from the binding constant measurements is crucial for the calculation of free drug concentration in plasma in order to predict/modify the dosage needed. In this study, a novel method Microscale Thermophoresis (MST) was applied in the investigation of molecular interaction between human plasma protein AGP and five drugs from four different drug classes. Thermophoresis describes a direct movement of molecules through a temperature gradient and is one of the two main factors contributing to the measured MST signal, the other being TRIC (Temperature- Related Intensity Change). AGP-drug binding constants are listed in the Table 1. Table 1. Drugs, drug classes and their respective binding constants on native human AGP. Drug Drug Class Kd / M Carvedilol Antihypertensive 1.13∙10^-4 ± 6.69∙10^-6 Dipyridamole Antithrombotic 2.96∙10^-6 ± 3.48∙10^-7 Imipramine hydrochloride Antidepressant 1.61∙10^-3 ± 1.88∙10^-4 Propranolol hydrochloride Antihypertensive 1.03∙10^-3 ± 5.04∙10^-5 Vinblastine sulfate Cytostatic 3.14∙10^-4 ± 2.10∙10^-5 [1] G. L. Trainor, Expert Opin. Drug Discov., 2(1) (2007) 51-64 [2] J. M. Kremer, J. Wilting, L. H. Janssen Pharmacol Rev.. 40(1) (1988) 1-47

Alpha-1-acid glycoprotein ; Drugs ; Binding

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