Toutain P L, Lefèbvre H P
UMR 181 Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, Toulouse cedex 03, France.
J Vet Pharmacol Ther. 2004 Dec;27(6):515-25. doi: 10.1111/j.1365-2885.2004.00601.x.
The pharmacokinetic (PK) properties and the pharmacokinetic/pharmacodynamic (PK/PD) relationships for the angiotensin-converting enzyme (ACE) inhibitors (ACEIs), such as enalaprilat, benazeprilat, imidaprilat and ramiprilat, differ from those of conventional drugs. This is because of their immediate and saturable binding to an ACE pool which is partly circulating (and contributing to the measured plasma concentration), and partly noncirculating (tissular), being anchored to the endothelium of vessels and not measurable by the analytical technique. A physiologically based model is required to allow appropriate interpretation of the different phases of the disposition curve of ACEI. The protracted terminal phase observed for all ACEIs is not a conventional elimination phase but a phase dependent on ACEI dissociation from ACE. In contrast, the phase which reflects ACEI elimination (and which is interpreted as a distribution phase for a conventional drug) has a short half-life, thus explaining the absence of drug accumulation during repeated dosing and mild kidney failure. ACE inhibition is the surrogate endpoint generally selected for establishing a PK/PD relationship and for simulating dosage regimen scenarios in order to decide on the appropriate dosage regimen for ACEIs.
血管紧张素转换酶（ACE）抑制剂（如依那普利拉、贝那普利拉、咪达普利拉和雷米普利拉）的药代动力学（PK）特性以及药代动力学/药效学（PK/PD）关系与传统药物不同。这是因为它们与ACE池的结合迅速且具有饱和性，ACE池部分处于循环状态（并影响所测得的血浆浓度），部分处于非循环状态（组织中），附着于血管内皮，无法通过分析技术进行测量。需要一个基于生理学的模型来对ACE抑制剂处置曲线的不同阶段进行恰当解释。所有ACE抑制剂观察到的持久终末相并非传统的消除相，而是一个取决于ACE抑制剂从ACE解离的阶段。相比之下，反映ACE抑制剂消除的阶段（对于传统药物被解释为分布相）半衰期较短，这就解释了重复给药和轻度肾衰竭期间无药物蓄积的现象。ACE抑制是通常选择用于建立PK/PD关系以及模拟给药方案情景以确定ACE抑制剂合适给药方案的替代终点。
