In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors
In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors
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DOI：
10.1016/j.ijpharm.2008.05.001
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发表时间：
2008-09-01
影响因子：
5.8
通讯作者：
Jung, Mira
中科院分区：
文献类型：
--
作者：
Konsoula, Roula;Jung, Mira
组蛋白去乙酰化酶抑制剂（HDACIs）是一类新型的抗肿瘤药物，对多种肿瘤具有较强的治疗作用。在本研究中，评价了两种基于巯基乙酰胺的HDACI（编码为W2和S2）的体外血浆稳定性、渗透性、溶解度和亲脂性（log D），并与伏立诺他（SAHA）进行了比较。结果表明，化合物在HCl（pH 1.2）中表现出高溶解度，但在PBS（pH 7.4）中的溶解度低于SAHA。此外，与SAHA相比，基于巯基乙酰胺的HDACI表现出更高的亲脂性值。使用Caco-2细胞单层作为肠粘膜模型评价这些化合物的渗透性。Caco-2研究表明，化合物S2和W2具有高度渗透性，顶侧至基底侧方向的表观渗透系数（P-app）分别为7.33 x 10（-6）和15.0 x 10（-6）cm/s。在人、小鼠、猪和大鼠血浆中测定了体外稳定性。数据显示，化合物W2在人和大鼠血浆中更稳定，S2在所有血浆物种中比SAHA更稳定。总之，这些结果表明基于巯基乙酰胺的HDACI具有有利的溶解性、亲脂性、渗透性和血浆稳定性特征。(C)2008 Elsevier B. V.保留所有权利。
Histone deacetylase inhibitors (HDACIs) are emerging as a new class of therapeutic agents with potent antitumor activities in a broad spectrum of human cancers. In this study, the in vitro plasma stability, permeability, solubility, and lipophilicity (log D) of two mercaptoacetamide-based HDACIs (coded as W2 and S2) were evaluated and compared to Vorinostat (SAHA). The results demonstrated that the compounds manifested high solubility in HCl (pH 1.2) but lower in PBS (pH 7.4) than SAHA. Moreover, mercaptoacetamide-based HDACIs exhibited higher lipophilicity values compared to SAHA. The permeability of these compounds was evaluated using the Caco-2 cell monolayer as a model of the intestinal mucosa. The Caco-2 studies revealed that the compounds S2 and W2 are highly permeable with apparent permeability coefficients (P-app) in the apical to basolateral direction of 7.33 x 10(-6) and 15.0 x 10(-6) cm/s, respectively. The in vitro stability was determined in human, mouse, porcine and rat plasma. Data showed that the compound W2 is more stable in human and rat plasma and the S2 is more stable in all plasma species than SAHA. Taken together, these results indicate that the mercaptoacetamide-based HDACIs possess favorable solubility, lipophilicity, permeability and plasma stability features. (C) 2008 Elsevier B.V. All rights reserved.