Plasma protein binding of bepridil.

Area of Science:

• Pharmacology
• Biochemistry
• Drug Metabolism

Background:

• Bepridil HCl is a calcium-channel blocking agent used clinically.
• Understanding drug-protein binding is crucial for predicting pharmacokinetics and pharmacodynamics.
• Plasma protein binding influences drug distribution, efficacy, and potential drug interactions.

Purpose of the Study:

• To investigate the extent and characteristics of bepridil HCl binding to human plasma proteins.
• To identify the primary plasma proteins involved in bepridil binding.
• To assess the influence of other substances and patient conditions on bepridil binding.

Main Methods:

• Utilized radiolabeled bepridil (bepridil-14C) for binding studies.
• Employed equilibrium dialysis to quantify unbound drug concentrations.
• Analyzed plasma from healthy subjects and angina patients.

Main Results:

• Over 99.7% of bepridil bound to human plasma proteins.
• High-affinity binding occurred on alpha1-acid glycoprotein (AAG) or an AAG-albumin complex.
• Lower affinity binding sites were identified on albumin and other macromolecules.
• Bepridil extensively distributed into erythrocytes, but high plasma protein binding limited blood concentrations.
• Protein binding was unaffected by nonesterified fatty acids.
• Displacement by verapamil, nifedipine, diltiazem, disopyramide, warfarin, and tris-(2-butoxyethyl)phosphate occurred only at supra-clinical concentrations.
• No significant differences in binding were observed between healthy subjects and angina patients.

Conclusions:

• Bepridil HCl exhibits extensive plasma protein binding, primarily to AAG.
• The high binding affinity suggests a significant role for AAG in bepridil disposition.
• Clinical drug interactions due to displacement are unlikely at therapeutic concentrations.
• Patient plasma demonstrated similar binding capacity to healthy subjects.