Modeling Cellular Pharmacokinetics of 14- and 15-membered Macrolides with Physicochemical Properties
| Autor: | Višnja Stepanić, Goran Kragol, Selvira Zulfikari, Mario Hlevnjak, Vesna Munić, Sanja Koštrun, Irena Ćaleta, Klára Valkó, Branka Tavčar, Oresta Makaruha-Stegić, Lara Mikac, Marko Dukši, Jovica Ralić, Iva Tatić, Kristina Butković, Ivica Malnar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Lung Neoplasms
Chemical Phenomena Chemistry Stereochemistry Primary Cell Culture Respiratory Mucosa Ring (chemistry) Models Biological Structure-Activity Relationship cellular pharmacokinetics macrolides modelling Cell culture Cell Line Tumor Drug Discovery Leukocytes Molecular Medicine Cellular pharmacokinetics Structure–activity relationship Humans Tissue distribution Macrolides Lung |
| DOI: | 10.1021/jm101317f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|