Evaluation of the pharmacokinetics of 2-carba-cyclic phosphatidic acid by liquid chromatography-triple quadrupole mass spectrometry
Evaluation of the pharmacokinetics of 2-carba-cyclic phosphatidic acid by liquid chromatography-triple quadrupole mass spectrometry
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DOI：
10.1016/j.prostaglandins.2020.106450
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发表时间：
2020-10-01
影响因子：
2.9
通讯作者：
Murakami-Murofushi, Kimiko
中科院分区：
文献类型：
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作者：
Shimizu, Yoshibumi;Fukasawa, Keiko;Murakami-Murofushi, Kimiko
环磷脂酸（cPA）是一种抑制癌症转移和骨关节炎的溶血磷脂介质。它在多发性硬化症和短暂性缺血后延迟性神经元死亡等疾病中也具有神经保护作用。为了利用cPA的特性开发新的治疗策略，我们合成了几种cPA衍生物，并发现了2-碳-cPA （2ccPA）作为一个有前途的候选。为了开发2ccPA作为治疗药物，本研究采用液相色谱-三重四极杆质谱法研究了2ccPA的药动学特征。2ccPA以1.6 mg/kg的剂量腹腔注射小鼠，2ccPA在血浆中的半衰期为16 min。2ccPA以16 mg/kg的剂量腹腔给药，给药后20 min分布于包括脑在内的各脏器。研究发现，2ccPA在中性或碱性条件下（如肠）是稳定的，但在酸性条件下（如胃）是不稳定的。当2ccPA以胃耐药形式以肠溶性胶囊口服给药给鼠时，血浆2ccPA水平在2小时达到峰值，此后缓慢下降，甚至在给药后10小时仍持续检测到。在这里，我们报告了从胶囊中持续释放2ccPA对降低大鼠溶血磷脂酶D活性和降低血浆溶血磷脂酸水平的影响。这些发现将有助于进一步研究评估2ccPA在几种疾病中的应用。
Cyclic phosphatidic acid (cPA) is a lysophospholipid mediator that suppresses cancer metastasis and osteoarthrills. It also has neuroprotective roles in diseases such as multiple sclerosis and delayed neuronal death following transient ischemia. In order to take advantage of the properties of cPA for the development of new therapeutic strategies, we have synthesized several cPA derivatives and discovered 2-carba-cPA (2ccPA) as a promising candidate. To develop 2ccPA as a therapeutic agent, we investigated the pharmacokinetic profile of 2ccPA by liquid chromatography-triple quadrupole mass spectrometry in this study. When 2ccPA was administered intraperitoneally to mice at a dose of 1.6 mg/kg, the half-life of 2ccPA in plasma was 16 min. The 2ccPA, dosed intraperitoneally to mice at 16 mg/kg, distributed to each organ including brain at 20 min after dosing. It was found that 2ccPA was stable in neutral or alkaline conditions (e.g., intestine) but unstable in acidic conditions (e.g., stomach). When 2ccPA was orally administrated to rats as a gastro-resistant form using an enterosoluble capsule, plasma 2ccPA levels peaked at 2 h, slowly declined thereafter and persistently detected even at 10 h after administration. Here, we present the findings on the effect of the continuous release of 2ccPA from the capsule to reduce the lysophospholipase D activity and also decrease plasma levels of lysophosphatidic acid in rat. These findings will be useful in further studies for evaluating the application of 2ccPA in several disorders.