GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
J Med Chem. 2011 Feb 10;54(3):719-33. doi: 10.1021/jm101317f. Epub 2011 Jan 5.
Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics. By comparison of cellular accumulation and retention in six human primary cell cultures of leukocytic and lung origin, as well as in lung carcinoma cell line NCI-H292, this cell line was found to be an adequate representative cell type for modeling macrolide cellular pharmacokinetics. Accumulation and retention in the NCI-H292 cells, as well as various physicochemical properties, were determined for a set of 48 rationally designed basic macrolide compounds. Classification models for predicting macrolide cellular accumulation and retention were developed using relatively easily determined and conceptually simple descriptors: experimentally determined physicochemical parameters ChromlogD and CHI IAM, as well as a calculated number of positively charged atoms (POS). The models were further tested and improved by addition of 37 structurally diverse macrolide molecules.
14 元和 15 元大环内酯类的特点是具有高而广泛的组织分布，以及良好的细胞积累和保留。由于大环内酯类结构不符合 Lipinski 的五规则，因此不能通过基于小分子数据的常见模型成功预测大环内酯类药代动力学特性。在这里，我们描述了第一个大环内酯类细胞药代动力学模型的开发。通过比较六种人原代白细胞和肺细胞培养物以及肺癌细胞系 NCI-H292 中的细胞积累和保留，发现该细胞系是建模大环内酯类细胞药代动力学的合适代表细胞类型。对一组 48 种合理设计的基本大环内酯化合物进行了 NCI-H292 细胞的积累和保留以及各种理化性质的测定。使用相对容易确定且概念简单的描述符（实验测定的理化参数 ChromlogD 和 CHI IAM 以及计算的正电荷原子数 POS）开发了用于预测大环内酯类细胞积累和保留的分类模型。通过添加 37 种结构多样的大环内酯类分子，进一步测试和改进了模型。
