title: Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties.
abstract: 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.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
authors.forename: Sanja
authors.initials: S
authors.lastname: Koštrun
authors.forename: Ivica
authors.initials: I
authors.lastname: Malnar
authors.forename: Mario
authors.initials: M
authors.lastname: Hlevnjak
authors.forename: Kristina
authors.initials: K
authors.lastname: Butković
authors.forename: Irena
authors.initials: I
authors.lastname: Ćaleta
authors.forename: Marko
authors.initials: M
authors.lastname: Dukši
authors.forename: Goran
authors.initials: G
authors.lastname: Kragol
authors.forename: Oresta
authors.initials: O
authors.lastname: Makaruha-Stegić
authors.forename: Lara
authors.initials: L
authors.lastname: Mikac
authors.forename: Jovica
authors.initials: J
authors.lastname: Ralić
authors.forename: Iva
authors.initials: I
authors.lastname: Tatić
authors.forename: Branka
authors.initials: B
authors.lastname: Tavčar
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
authors.forename: Selvira
authors.initials: S
authors.lastname: Zulfikari
authors.forename: Vesna
authors.initials: V
authors.lastname: Munić
mesh_terms: D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008175:Lung Neoplasms; D018942:Macrolides / Q000737:chemistry / Q000493:pharmacokinetics*; D008954:Models, Biological; D061251:Primary Cell Culture; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018942:Macrolides