Structural properties governing drug-plasma protein binding determined by high-performance liquid chromatography...

Area of Science:

• Pharmacology
• Analytical Chemistry
• Biochemistry

Background:

• Drug-plasma protein binding influences drug distribution, efficacy, and toxicity.
• Understanding these interactions is crucial for drug development and personalized medicine.

Purpose of the Study:

• To investigate the structural properties governing drug-plasma protein binding using HPLC.
• To quantitatively determine the effect of ionized species on plasma protein binding.

Main Methods:

• High-performance liquid chromatography (HPLC) with immobilized human serum albumin (HSA) and alpha1-acid glycoprotein (AGP) stationary phases.
• Abraham linear free energy relationship (LFER) analyses of retention factors for 65 diverse compounds.
• Quantitative analysis of interactions for both neutral and ionized drug species.

Main Results:

• McGowan's characteristic molecular volume (V), dipolarity/polarizability (S), and hydrogen bond basicity (B) are key descriptors for neutral compounds interacting with HSA and AGP.
• Hydrogen bond acidity (A) and excess molar refraction (E) were less significant for neutral compounds.
• Ionized acids bind strongly to HSA, and ionized bases bind strongly to AGP, with ionized forms driving increased binding.

Conclusions:

• Molecular descriptors V, S, and B are critical for predicting drug interactions with plasma proteins for neutral compounds.
• The ionization state of a drug significantly impacts its binding affinity to plasma proteins, particularly for acidic drugs binding to HSA.