McGowan F X, Reiter M J, Pritchett E L, Shand D G
Clin Pharmacol Ther. 1983 Apr;33(4):485-90. doi: 10.1038/clpt.1983.66.
The relationship between alpha 1-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 less than 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.
在15名受试者静脉注射10毫克维拉帕米15分钟后采集的样本中，研究了α1-酸性糖蛋白（AAG）血浆浓度与血浆维拉帕米结合之间的关系。结合率与AAG浓度之间存在良好的相关性（r = 0.83），表明AAG可以结合维拉帕米。通过向白蛋白溶液中添加AAG在体外证实了这一点，这导致结合率（r = 0.99）与AAG浓度之间存在很强的相关性。在7名受试者静脉注射10毫克维拉帕米后，还多次研究了游离和总血浆浓度与维拉帕米对PR间期影响之间的关系。虽然两种浓度的对数与PR间期延长百分比之间存在相关性（P小于0.001），但游离药物浓度（r2 = 0.58）的相关性比总血浆浓度（r2 = 0.36）更强。与给定效应（220%）相关的游离浓度范围也比总浓度（300%）窄。虽然这些数据表明AAG是血浆维拉帕米结合变异性的主要原因，这反过来又在一定程度上导致了给定总血浆浓度有效性的变化，但对于除心律失常外其他方面健康的患者，这些个体变异原因都不太可能产生重大临床影响。
