Bree F, Nguyen P, Urien S, Resplandy G, Tillement J P
Département de Pharmacologie, Faculté de Médecine, Paris XII, Créteil, France.
Int J Clin Pharmacol Ther Toxicol. 1992 Sep;30(9):325-30.
The bindings of perindopril and of its active metabolite perindoprilat to human serum, isolated proteins and to erythrocytes were studied by equilibrium dialysis. Within the therapeutic concentrations range, perindopril was 74% bound to serum involving a non-saturable process, NKa = 2.87. The main binders are serum albumin and alpha 1-acid glycoprotein. The serum binding of perindoprilat involved two successive steps. First, a saturable high-affinity binding (Ka: 2.8 x 10(9) M-1) occurred, involving probably the angiotensin converting enzyme (ACE). The second binding step was non-saturable with a very weak binding capacity, NKa = 0.15, quite superimposable to the HSA bound perindoprilat. Free fatty acids (FFA) did not alter the binding to HSA. The binding of both compounds to erythrocytes was low especially with perindopril, when measured in the presence of plasma. A significant correlation showed that the overall serum binding percentage of both drugs was essentially determined by HSA concentration. Serum binding was decreased in renal failure or cirrhosis, this result was principally linked to the hypoalbuminemia. Interactions with other drugs were limited to the binding of salicylate, tolbutamide and digitoxin to HSA.
通过平衡透析研究了培哚普利及其活性代谢产物培哚普利拉与人血清、分离的蛋白质和红细胞的结合情况。在治疗浓度范围内，培哚普利与血清的结合率为74%，涉及一个非饱和过程，NKa = 2.87。主要的结合蛋白是血清白蛋白和α1-酸性糖蛋白。培哚普利拉与血清的结合涉及两个连续步骤。首先，发生一个可饱和的高亲和力结合（Ka：2.8×10⁹ M⁻¹），可能涉及血管紧张素转换酶（ACE）。第二个结合步骤是非饱和的，结合能力非常弱，NKa = 0.15，与结合在人血清白蛋白（HSA）上的培哚普利拉相当。游离脂肪酸（FFA）不会改变其与HSA的结合。在血浆存在的情况下进行测量时，这两种化合物与红细胞的结合率都很低，尤其是培哚普利。显著的相关性表明，这两种药物的总体血清结合率基本上由HSA浓度决定。肾衰竭或肝硬化时血清结合率降低，这一结果主要与低白蛋白血症有关。与其他药物的相互作用仅限于水杨酸盐、甲苯磺丁脲和地高辛与HSA的结合。
