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Modeling Cellular Pharmacokinetics of 14- and 15-membered Macrolides with Physicochemical Properties


Stepanić, Višnja; Koštrun, Sanja; Malnar, Ivica; Hlevnjak, Mario; Butković, Kristina; Ćaleta, Irena; Dukši, Marko; Kragol, Goran; Makaruha-Stegić, Oresta; Mikac, Lara et al.
Modeling Cellular Pharmacokinetics of 14- and 15-membered Macrolides with Physicochemical Properties // Journal of medicinal chemistry, 54 (2011), 3; 719-733 doi:10.1021/jm101317f (međunarodna recenzija, članak, znanstveni)


Naslov
Modeling Cellular Pharmacokinetics of 14- and 15-membered Macrolides with Physicochemical Properties

Autori
Stepanić, Višnja ; Koštrun, Sanja ; Malnar, Ivica ; Hlevnjak, Mario ; Butković, Kristina ; Ćaleta, Irena ; Dukši, Marko ; Kragol, Goran ; Makaruha-Stegić, Oresta ; Mikac, Lara ; Ralić, Jovica ; Tatić, Iva ; Tavčar, Branka ; Valko, Klara ; Zulfikari, Selvira ; Munić. Vesna

Izvornik
Journal of medicinal chemistry (0022-2623) 54 (2011), 3; 719-733

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Cellular pharmacokinetics; macrolides; modelling

Sažetak
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 into the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe development of the first models for macrolide cellular pharmacokinetics. Comparing cellular accumulation and retention in 6 human primary cell cultures of leukocytic and lung origin, as well as in lung carcinoma cell line NCI-H292, this cell line was found as an adequate representative cell type for investigating 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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija



POVEZANOST RADA


Projekt / tema
098-0982464-2511 - Epigenetičke i imunomodulatorne promjene u zloćudnim tumorima glave i vrata (Koraljka Gall-Trošelj, )

Ustanove
Institut "Ruđer Bošković", Zagreb,
Fidelta d.o.o.

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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