Belz G G, Kirch W, Kleinbloesem C H
Zentrum für Kardiovaskuläre Pharmakologie, ZeKaPha GmbH, Wiesbaden, Federal Republic of Germany.
Clin Pharmacokinet. 1988 Nov;15(5):295-318. doi: 10.2165/00003088-198815050-00003.
The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.
本文综述了血管紧张素转换酶（ACE）抑制剂的药代动力学与药效学行为之间的相互关系。首先，介绍了一些用于评估ACE抑制剂在人体中药效学的方法。这些方法包括体液分析（如血浆中的ACE活性、肾素活性等）、血流动力学变化（血压、总外周阻力等）以及激动剂激发试验（输注血管紧张素I）。随后，基于ACE抑制后获得的生化过程描述了一个药代动力学-药效学模型，该模型似乎有助于解释复杂的过程。基于此模型，讨论了一方面血浆药物浓度与另一方面血浆ACE活性、血浆或血液中血管紧张素II浓度或血压之间的各种相关性。从所获得的模型可以明显看出，在许多情况下，抑制剂从ACE结合物上的释放是实际上决定低浓度药物药效学相关消除速率的步骤，而在高浓度时，药物的消除主要取决于肾脏（和/或肝脏）的消除速率。接着阐述了一些ACE抑制剂在各种疾病状态下的动态-动力学相关性：动脉高血压、心力衰竭、老年、肾衰竭、肝脏疾病。在最后一部分，描述了ACE抑制剂与食物和其他药物相互作用的动力学和动态相关性（如前列腺素抑制剂、利尿剂、地高辛和西咪替丁）。尽管有大量文献涉及ACE抑制剂的动力学和/或动态特性，但对其动力学和动态行为之间关系的精确了解相当有限，显然需要进一步研究以阐明这个复杂的主题，从而改善使用这些有用新化合物的治疗可能性。
