engleski

Effect of the sialic acid residues upon the binding of beta blocker propranolol to human serum alpha-1 acid glycoprotein

Plasma protein binding is a focus of great importance in the pharmaceutical science. Alpha- acid glycoprotein (AGP) is largely selective for basic and neutral drugs like propranolol (PRO). In healthy patients, the basal plasma concentration of AGP is approximately 20 mM, whereas in some disease states it can increase up to 7-fold. Since the carbohydrate content of AGP is 45 %, which contains 14 sialic acid residues per molecule, it is believed that those residues might cause different binding affinity of drugs. As such, the free fraction of drug could change in plasma, which then affects the pharmacokinetics of drug itself. Determination of thermodynamic parameters, such as dissociation constant, could be valuable in preclinical studies where it is important to know the exact dosage of drug. Therefore, isothermal titration calorimetry (ITC) is very useful in the evaluation of thermodynamic parameters needed in drug development and further in dose optimization as well. The purpose of this study was to elucidate the binding mechanism and related interactions of PRO with AGP. We first investigated the binding of PRO with native AGP using ITC. The effect of sialic acid residues on the binding of PRO to AGP was then examined using desialylated AGP.

alpha-1 acid glycoprotein ; propranolol ; drug binding ; ITC method ; plasma protein ; binding mode

nije evidentirano