Structural properties governing drug-plasma protein binding determined by high-performance liquid chromatography method.
The high-performance liquid chromatography (HPLC) method employing stationary phases immobilized with plasma proteins was used for this study to investigate the structural properties governing drug-plasma protein binding. A set of 65 compounds with a broad range of structural diversity (in terms of volume, hydrogen-bonding, polarity and electrostatic force) were selected for this purpose. The Abraham linear free energy relationship (LFER) analyses of the retention factors on the immobilized HSA (human serum albumin) and AGP (α1-acid glycoprotein) stationary phases showed that McGowan's characteristic molecular volume (V), dipolarity/polarizability (S) and hydrogen bond basicity (B) are the three significant molecular descriptors of solutes determining the interaction with immobilized plasma proteins, whereas excess molar refraction (E) is less important and hydrogen bond acidity (A) is not of statistical significance in both systems, for electrically neutral compounds. It was shown that ionised acids, as carboxylate anions, bind very strongly to the immobilized HSA stationary phase and that ionised bases, as cations bind strongly to the AGP stationary phase. This is the first time that the effect of ionised species on plasma protein binding has been determined quantitatively; the increased binding of acids to HSA is due almost entirely to acids in their ionised form.
['Kamble|Sharad|S|', 'Loadman|Paul|P|', 'Abraham|Michael H|MH|', 'Liu|Xiangli|X|']
D000838:Anions D002412:Cations D002851:Chromatography, High Pressure Liquid D055808:Drug Discovery D006801:Humans D006860:Hydrogen Bonding D006863:Hydrogen-Ion Concentration D008956:Models, Chemical D009961:Orosomucoid D010599:Pharmacokinetics D011485:Protein Binding D021281:Quantitative Structure-Activity Relationship D000075462:Serum Albumin, Human
Binding HPLC Plasma proteins Linear free energy relationship Abraham (Absolv) descriptors Retention factors (k)