Characterization of basic drug–human serum protein interactions by capillary electrophoresis

Abstract

Drug-protein interactions are determining factors in the therapeutic, pharmacodynamic and toxicological drug properties. The affinity of drugs towards plasmatic proteins is apparently well established in bibliography. Albumin (HSA) especially binds neutral and negatively charged compounds; alpha(1)-acid glycoprotein (AGP) binds many cationic drugs, lipoproteins bind to nonionic and lipophilic drugs and some anionic drugs while globulins interact inappreciably with the majority of drugs. In this paper, the characterization of the interaction between cationic drugs, beta-blockers and phenotiazines towards HSA, AGP, and both HSA + AGP mixtures of proteins under physiological conditions by CE-frontal analysis is presented. Furthermore, the binding of these drugs to all plasmatic proteins is evaluated by using ultrafiltration and CE. The results indicate that the hydrophobic character of compounds seems to be the key factor on the interaction between cationic drugs towards proteins. In fact, hydrophobic basic drugs bind in great extension to HSA, while hydrophilic basic drugs present low interactions with proteins and bind especially to AGP.

Kinetic Capillary Electrophoresis with Mass‐Spectrometry Detection (KCE‐MS) Facilitates Label‐Free Solution‐Based Kinetic Analysis of Protein–Small Molecule Binding

“…Although it is worth mentioning that previously published results obtained with another label-free method (affinity CE) are closer to the KCE-MS results: 46 mm for labetalol and 33 mm for pindolol. [20] We thus conclude that this initial validation of KCE-MS is satisfactory and sufficient to continue efforts in further development of this new method.…”

“…AGP is a highly abundant plasma protein with a typical concentration of 0.4-1.0 g L À1 ; it is the major binding protein for cationic small molecules in the human body. [19,20] Figure 2 shows calibration/optimization of MS for propranolol. www.chembiochem.org Figure 3 illustrates the determination of the three fraction-collection windows for studying the interaction between AGP and propranolol.…”

CE at the omics level: Towards systems biology – An update

“…HSA, in particular, binds neutral-and negatively charged compounds; AGP binds many cationic drugs and lipoproteins bind to nonionic and lipophilic drugs and some anionic drugs, while globulins interact inappreciably with the majority of drugs. Martínez-Gómez et al [135] presented the characterization of the interaction between cationic drugs, b-blockers, and phenotiazines toward HSA, AGP, and mixtures of both HSA and AGP under physiological conditions using CE-frontal analysis. Martínez-Gómez et al [136] also used CE to characterize the interaction between antihistamines (cationic drugs) toward HSA and AGP under physiological conditions.…”

Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide

“…SA20 is one of many synthetic peptides discovered using phage display that binds to serum albumin in an apparently noncompetitive manner (Dennis et al 2002). The 20 amino acid disulfide-constrained peptide (QRLIEDICLPRWGCLWEDDF) is primarily composed of lipophilic residues (Leu, Ile, Cys, Trp, Phe) and anionic residues (Glu, Asp), which contribute to increased serum albumin binding (Martinez-Gomez et al 2006). The purpose of this investigation was to determine whether the PKs of hPRL, hGH, and their antagonists, hPRL-G129R and hGH-G120R, could be enhanced by fusing a small serum albuminbinding peptide, SA20, to their amino-or carboxyl-terminus.…”