Pharmacokinetics and Pharmacodynamics of Recombinant Human Angiotensin-Converting Enzyme 2 in Healthy Human Subjects
Pharmacokinetics and Pharmacodynamics of Recombinant Human Angiotensin-Converting Enzyme 2 in Healthy Human Subjects
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DOI：
10.1007/s40262-013-0072-7
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发表时间：
2013-09-01
影响因子：
4.5
通讯作者：
Kraehenbuehl, Stephan
中科院分区：
文献类型：
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作者：
Haschke, Manuel;Schuster, Manfred;Kraehenbuehl, Stephan
血管紧张素转换酶2（ACE 2）将血管紧张素II（Ang 1 -8）转化为血管紧张素1-7（Ang 1 -7），后者是Ang 1 -8的功能性拮抗剂，具有血管舒张、抗增殖、抗血管生成和抗炎特性。在具有升高的Ang 1 -8的不平衡的肾素-血管紧张素-醛固酮系统的情况下，给予ACE 2在多种动物模型中显示出有希望的效果。通过外源性给予ACE 2来增强ACE 2活性也可能有益于具有病理性升高的Ang 1 -8的人类疾病。作为第一步，我们进行了首次在人体研究，以确定健康志愿者的药代动力学，药效学，安全性和耐受性的重组人ACE 2（rhACE 2）静脉注射给药的健康人类受试者在一个随机，双盲，安慰剂对照，单剂量，剂量递增的研究，然后开放标签的多剂量研究。通过定量血浆样品中的ACE 2活性和ACE 2含量来确定ACE 2浓度。使用液相色谱-串联质谱法测定血管紧张素系统效应肽Ang 1 -8、Ang 1 -7和Ang 1 -5的浓度。100- 1，200 μ g/kg的rhACE 2单次给药引起剂量依赖性的全身暴露增加，伴有双相消除和10 h的剂量非依赖性终末半衰期。在所有单次给药队列中，血管紧张素1 -8在输注后30分钟内降低，血管紧张素1-7（Ang 1 -7）增加（100和200 μ g/kg剂量）、降低或保持不变（400- 1，200 μ g/kg剂量），而血管紧张素1-5（Ang 1 -5）在所有研究剂量下一过性增加。除最低rhACE 2剂量外，Ang 1 -8水平的下降持续至少24小时。重复给药（400 μ g/kg，持续3或6天）仅引起ACE 2的最小积累，并且在整个施用期间Ang 1 -8水平被抑制。暴露具有剂量依赖性，终末消除半衰期在10 h范围内，与剂量无关。尽管血管紧张素系统肽浓度有显著变化，但不存在心血管效应，表明健康志愿者存在有效的代偿机制。
Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), a functional antagonist of Ang1-8, with vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties. In conditions with an unbalanced renin-angiotensin-aldosterone system with elevated Ang1-8, administration of ACE2 has shown promising effects in a variety of animal models. Enhancing ACE2 activity by exogenous administration of ACE2 might also be beneficial in human diseases with pathologically elevated Ang1-8. As a first step we performed a first-in-man study to determine pharmacokinetics, pharmacodynamics, safety, and tolerability of recombinant ACE2 in healthy volunteers.Recombinant human ACE2 (rhACE2) was administered intravenously to healthy human subjects in a randomized, double-blind, placebo-controlled, single-dose, dose-escalation study followed by an open-label multiple-dose study. ACE2 concentrations were determined by quantifying ACE2 activity and ACE2 content in plasma samples. Concentrations of the angiotensin system effector peptides Ang1-8, Ang1-7, and Ang1-5 were determined using a liquid chromatography-tandem mass spectrometry method.Single rhACE2 doses of 100-1,200 mu g/kg caused a dose-dependent increase of systemic exposure with biphasic elimination and a dose-independent terminal half-life of 10 h. In all single-dose cohorts, Ang1-8 decreased within 30 min postinfusion, angiotensin 1-7 (Ang1-7) either increased (100 and 200 mu g/kg doses), decreased, or remained unchanged (400-1,200 mu g/kg doses), whereas angiotensin 1-5 (Ang1-5) transiently increased for all doses investigated. With the exception of the lowest rhACE2 dose, the decrease in Ang1-8 levels lasted for at least 24 h. Repeated dosing (400 mu g/kg for 3 or 6 days) caused only minimal accumulation of ACE2, and Ang1-8 levels were suppressed over the whole application period.Administration of rhACE2 was well tolerated by healthy human subjects. Exposure was dose dependent with a dose-independent terminal elimination half-life in the range of 10 h. Despite marked changes in angiotensin system peptide concentrations, cardiovascular effects were absent, suggesting the presence of effective compensatory mechanisms in healthy volunteers.