Brockmeier D
Clinical Research, Hoechst AG, Frankfurt am Main, Germany.
Int J Clin Pharmacol Ther. 1995 Dec;33(12):631-8.
The pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors are often difficult to characterize using standard tools. Most of the problems arise from the tight binding of ACE inhibitors to ACE. The present paper discusses how tight binding of ramiprilat to ACE affects the pharmacokinetic characteristics and in vitro measurement of ACE inhibition. Data from a randomized crossover study in healthy volunteers given 2 different dosage forms with 5 mg ramipril serve to compare the theoretically deduced predictions with actual measurements. The data confirm that elimination is concentration-dependent and that therefore the pharmacokinetics are non-linear. Renal clearance increases with concentration. With respect to pharmacodynamics, free ramiprilat depletion due to tight binding is the reason for the steep nature of concentration-effect curves often observed for ACE inhibition. This type of relationship, however, cannot be described by the classical Emax model nor by the sigmoid Emax model. The model of tight binding presented shows that the concentration-effect curve becomes steeper the larger the concentration of ACE and the greater the affinity of the inhibitor to the target molecule. With the classical Emax model the concentration can be doubled about 3 times to increase the measurable effect from 10 to 50% maximum effect, and because the relationship is symmetric at the EC50% point of inflection, the concentration can be doubled another 3 times to increase the effect from 50 to 90%. With the tight-binding concentration-effect relationship, doubling the concentration about 3 times may also increase the effect from 10 to 50% of the maximum effect, a further doubling of the dose, however, causes a steep increase of the effect from 50 to nearly 100%. This tight-binding concentration-effect relationship may also be present in other classes of drugs.
血管紧张素转换酶（ACE）抑制剂的药代动力学通常很难用标准工具来表征。大多数问题源于ACE抑制剂与ACE的紧密结合。本文讨论了雷米普利拉与ACE的紧密结合如何影响药代动力学特征以及ACE抑制的体外测量。来自健康志愿者的一项随机交叉研究的数据，这些志愿者服用了含5毫克雷米普利的2种不同剂型，用于将理论推导的预测结果与实际测量结果进行比较。数据证实消除是浓度依赖性的，因此药代动力学是非线性的。肾清除率随浓度增加。关于药效学，由于紧密结合导致的游离雷米普利拉耗竭是ACE抑制中经常观察到的浓度-效应曲线陡峭性质的原因。然而，这种类型的关系既不能用经典的Emax模型也不能用S形Emax模型来描述。所提出的紧密结合模型表明，ACE浓度越高且抑制剂与靶分子的亲和力越大，浓度-效应曲线就越陡峭。用经典的Emax模型，浓度可以翻倍约3次，以使可测量的效应从最大效应的10%增加到50%，并且由于该关系在EC50%拐点处是对称的，浓度可以再翻倍3次，以使效应从50%增加到90%。对于紧密结合的浓度-效应关系，浓度翻倍约3次也可能使效应从最大效应的10%增加到50%，然而，剂量进一步翻倍会导致效应从50%急剧增加到近100%。这种紧密结合的浓度-效应关系也可能存在于其他类别的药物中。
