Predicting Drug Binding to Human Serum Albumin and Alpha One Acid Glycoprotein in Diseased and Age Patient Populations

Abstract

Plasma protein binding, namely the fraction unbound (f_u), can be an important determinant of the disposition and response of drugs. The primary objective of this study was to predict f_u values of 183 drugs utilizing either a single binding protein model, where the predominant binding protein had been established, or a multiple binding protein model (MBPM), where the relative binding contribution of human serum albumin (HSA) or alpha 1 acid glycoprotein (AAG) is known. Mean protein concentrations, dependent on disease or age, were used to account for changes in f_u. A simple scaling approach for binding protein concentration was employed to account for quantitative changes in molar concentrations of either HSA or AAG in their respective conditions. The MBPM predictive model works best if the relative binding contribution of HSA and AAG is known, and a scaler for the change in protein concentration can be adjusted accordingly. The value of MBPM was most evident when considering reported changes in lidocaine binding because of increasing AAG concentration in response to trauma. The present approach enhances the ability to predict f_u in diseased and age populations because of quantitative changes in major binding proteins.