Verapamil plasma binding: Relationship to α1‐acid glycoprotein and drug efficacy

The relationship between α1-acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P < 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy. Clinical Pharmacology and Therapeutics (1983) 33, 485–490; doi:10.1038/clpt.1983.66