Statin Lipophilicity as a Determinant of Drug Airway Distribution: A Pilot Study to Identify the Most Potent Statin(s) for the Treatment of Severe Asthma.

项目摘要 我们已经确定了他汀类药物（“他汀类药物”）作为一种潜在的重症哮喘患者的预防性治疗。 他汀类药物在许多不同的动物疾病模型中发挥有效的抗炎和免疫调节作用 包括哮喘。甲羟戊酸（MA）是HMG-CoA还原酶（HMGCR）的直接产物， 代谢为细胞信号传导和多种细胞功能的必需代谢物。所有他汀类药物均抑制HMGCR， 胆固醇生物合成的限速步骤。使用我们的哮喘小鼠模型，我们发现， 用他汀类药物产生MA可消除过敏原诱导的嗜酸性粒细胞增多、杯状细胞化生和气道炎症 反应过度多项回顾性临床研究显示，他汀类药物的使用与 改善哮喘的结果，包括类固醇节省效果。然而，一些小型随机临床试验 使用他汀类药物的随机对照试验（RCT）产生了相互矛盾的结果。研究设计、他汀类药物（亲脂性与 亲水性）、缺乏哮喘表型和治疗持续时间短可能是这些不确定的原因 调查结果。根据药物亲脂性选择他汀类药物在设计哮喘时是一个未得到充分重视的变量 试验，并且可能是关于哪种他汀类药物在气道中达到最高浓度的关键决定因素 车厢如果他汀类药物在哮喘中具有临床益处，它们必须首先以较高的速率到达气道。 足够的浓度（即“气道分布”）以进行治疗。考虑到他汀类药物的肝外外周 组织分布可以根据药物亲脂性而变化，最亲脂的他汀类药物如辛伐他汀是 预计达到比亲水性他汀类药物（如瑞舒伐他汀）更高的外周组织水平。然而，在这方面， 我们不知道这种现象是否发生在人的肺和呼吸道中，因为它从未被测量过。 我们的初步数据显示，他汀类药物的亲脂性越大，（i）气道上皮药物 浓度在严重哮喘，和（ii）更大的抗炎效力在体内。所以我们的 中心假设是亲脂性他汀类药物将达到显著更高的气道上皮浓度， 比亲水性他汀类药物更好的治疗效果。我们将用两个目标来检验这个假设：目标1： 在一项前瞻性初步研究中确定哪类他汀类药物具有最大的气道分布， 接受选择性支气管镜检查的人类受试者。目的2：确定哪类他汀类药物具有 在慢性过敏原诱导的哮喘小鼠模型中的最大功效。完成这项工作将 允许我们选择正确的他汀类药物，因此，直接告知即将推出的他汀类药物的合理设计 治疗严重哮喘的临床试验。这种知识也可能延伸到其他肺或气道 可能从他汀类药物治疗中获益的疾病。

PROJECT SUMMARY We have identified the statin drugs (`statins') as a potential adjunctive therapy for patients with severe asthma. Statins exert potent anti-inflammatory and immune modulatory effects in many different animal disease models including asthma. Mevalonate (MA) is the immediate product of HMG-CoA reductase (HMGCR) which is metabolized to essential metabolites for cell signaling and diverse cellular functions. All statins inhibit HMGCR, the rate-limiting step in cholesterol biosynthesis. Using our asthma mouse model, we showed that blockade of MA production with a statin abrogates allergen-induced eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Multiple retrospective clinical studies have shown a positive correlation between statin use and improved asthma outcomes, including steroid-sparing effects. However, several small randomized clinical trials (RCTs) using statins have yielded conflicting results. Differences in study design, statin class (lipophilic vs. hydrophilic), lack of asthma phenotyping, and short treatment durations may account for these inconclusive findings. The choice of statin based on drug lipophilicity is an underappreciated variable in designing asthma trials, and may be a key determinant regarding which statin achieves the highest concentrations in the airway compartment. If statins are to have a clinical benefit in asthma, they must first reach the airways in high enough concentrations (i.e. “airway distribution”) to be therapeutic. Given that statins' extrahepatic peripheral tissue distribution can vary according to drug lipophilicity, the most lipophilic statins like simvastatin are predicted to achieve higher peripheral tissue levels than the hydrophilic statins such as rosuvastatin. However, we do not know if this phenomenon occurs in the human lung and airways since it has never been measured. Our preliminary data show that the greater the statin lipophilicity, (i) the greater the airway epithelial drug concentration in severe asthmatics, and (ii) the greater its anti-inflammatory potency in vivo. Therefore, our central hypothesis is that lipophilic statins will achieve significantly higher airway epithelial concentrations and greater therapeutic efficacy than the hydrophilic statins. We will test this hypothesis with two Aims: Aim 1: To determine which class of statins has the greatest airway distribution in a prospective pilot study of human subjects undergoing elective bronchoscopy. Aim 2: To determine which class of statins has the greatest efficacy in a mouse model of chronic allergen-induced asthma. Accomplishing this work will allow us to select the right statin(s), and therefore, directly inform the rational design of forthcoming statin clinical trials for the treatment of severe asthma. This knowledge may also extend to other lung or airway diseases that could potentially benefit from treatment with statins.