A Model-Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
| Autor: | Ilse R. Dubbelboer, Elsa Lilienberg, Hans Lennernäs, Erik Sjögren |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Physiologically based pharmacokinetic modelling
Swine Metabolite Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Models Biological 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Drug Discovery medicine Animals Bile Doxorubicin Tissue Distribution Binding site Kidney Binding Sites biology Topoisomerase medicine.anatomical_structure chemistry Liver 030220 oncology & carcinogenesis Biophysics biology.protein Molecular Medicine Intracellular medicine.drug |
| Zdroj: | Molecular pharmaceutics. 14(3) |
| ISSN: | 1543-8392 |
| Popis: | Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conv... |
| Databáze: | OpenAIRE |
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