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首页> 外文期刊>International journal of clinical pharmacology and therapeutics >Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition.
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Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition.

机译：Moexipril显示出与延长的药代动力学半衰期和延长的ACE抑制作用有关的作用持续时间。

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OBJECTIVE: To characterize the lipophilic ACE inhibitor moexipril and its active metabolite moexiprilat regarding the duration of action, the susceptibility of the pharmacokinetics and pharmacodynamics to food intake and the concentration-dependent effect. METHODS: Three independent, open, randomized studies were performed in healthy subjects using crossover or parallel-group designs. In the first study, pharmacokinetics (AUC, Cmax, tmax, t 1/2) and ACE inhibition (up to 72 h) were investigated following single oral doses of 15 mg moexipril administered in the fasting and postprandial state (n = 24). The individual ACE inhibition data and plasma concentration data were fitted to an Emax model. In the second study, carried out in 52 volunteers, the pharmacokinetics were followed over 36 h following administration of 2 single oral doses of 15 mg moexipril. In the third study, the pharmacokinetics after multiple dosing of 15 mg moexipril once daily for 5 days were investigated in 12 young and 12 elderly subjects. RESULTS: Moexiprilat tmax was 1.5-2 h with only minor differences between single and multiple dosing. Compared to fasting, the postprandial moexiprilat Cmax and AUC (ratio fed/fasted 58.0%; 90% CI 52.2-64.5%) were distinctly reduced (ANOVA p = 0.0001). Moexiprilat showed a biphasic elimination phase with an average t 1/2 of 29-30 h. In contrast to the alpha-phase, the plasma concentrations during the terminal elimination phase were not affected by food. A relationship between ACE inhibition and plasma concentration was not observed. The average ACE inhibition over 72 h was 71 % in the fasting state and 74% in the postprandial state. ACE inhibition increased to about 80% after 24 h and decreased to about 60% at 72 h. The S-shaped concentration-effect curve indicated that a moexiprilat level of 1.3 ng/ml was sufficient to produce 50% inhibition of ACE. With repeated dosing there were no signs of drug accumulation and day-to-day drug levels were relatively constant. The trough concentrations at 24 h did not fall below the limit of 1-2 ng/ml, i.e. a 50% ACE inhibition. CONCLUSION: Moexiprilat showed an extended duration of action owing to a long terminal pharmacokinetic half-life and produced a persistent ACE inhibition. Although the pharmacokinetics were partly influenced by food intake, ACE inhibition was not affected. This might be explained by a second compartment directly related to the ACE which is less prone to food effects and the reaching of a ceiling in the sigmoidal concentration-effect curve even with the lower Cmax concentrations associated with the postprandial state.
机译：目的：从作用的持续时间，对食物摄入的药代动力学和药效学敏感性以及浓度依赖性的作用来表征亲脂性ACE抑制剂moexipril及其活性代谢物moexiprilat。方法：采用交叉或平行组设计对健康受试者进行了三项独立，开放，随机的研究。在第一个研究中，在禁食和餐后状态（n = 24）下单次口服15 mg莫西普利后，研究了药代动力学（AUC，Cmax，tmax，t 1/2）和ACE抑制（长达72小时）。将各个ACE抑制数据和血浆浓度数据拟合到Emax模型。在第二项研究中，对52名志愿者进行了研究，在服用2次单次口服剂量的15 mg莫西普利后，在36小时内跟踪了药代动力学。在第三项研究中，对12名年轻受试者和12名老年受试者进行了每天15 mg莫西普利5次每天多次给药后的药代动力学研究。结果：Moexiprilat tmax为1.5-2 h，单次和多次给药之间仅有微小差异。与禁食相比，餐后moexiprilat Cmax和AUC（进食/禁食之比58.0％; 90％CI 52.2-64.5％）明显降低（ANOVA p = 0.0001）。莫西普利拉特显示出双相消除阶段，平均t 1/2为29-30小时。与α相相反，最终消除相期间的血浆浓度不受食物的影响。没有观察到ACE抑制与血浆浓度之间的关系。在禁食状态下72小时内的平均ACE抑制率为71％，在餐后状态下为74％。 ACE抑制作用在24小时后增加到约80％，在72小时后减少到约60％。 S形的浓度效应曲线表明，莫西普利特水平为1.3ng / ml足以产生50％的ACE抑制。通过重复给药，没有药物蓄积的迹象，并且日常药物水平相对恒定。 24小时的谷浓度不低于1-2ng / ml的极限，即50％ACE抑制。结论：由于长期的药代动力学半衰期长，Moexiprilat的作用持续时间延长，并产生持续的ACE抑制作用。尽管药代动力学部分受食物摄入量的影响，但ACE抑制作用不受影响。这可能是由于与ACE直接相关的第二个隔间可以解释的，即使在餐后状态下Cmax浓度较低的情况下，第二个隔间也较不易产生食物效应，也无法达到S型浓度效应曲线的上限。

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