000145999 001__ 145999
000145999 005__ 20241122150934.0
000145999 037__ $$aTAZ-TFM-2023-378
000145999 041__ $$aeng
000145999 1001_ $$aGarcía Gadea, Sara
000145999 24200 $$aImpact of plasma protein binding on hepatic uptake and on the in vitro - in vivo extrapolation of clearance
000145999 24500 $$aImpacto de la unión a proteínas en la captación hepática y en la extrapolación in vitro - in vivo de la eliminación
000145999 260__ $$aZaragoza$$bUniversidad de Zaragoza$$c2023
000145999 506__ $$aby-nc-sa$$bCreative Commons$$c3.0$$uhttp://creativecommons.org/licenses/by-nc-sa/3.0/
000145999 520__ $$aDrug discovery and development is a long and expensive process. Consequently, it is critical to identify and deprioritize failure molecules with unfavorable properties as early as possible in the pipeline. Clearance is one of the key parameters that is used to decide which drug candidates to move forward in the pipeline, as it measures the ability of the body to eliminate a drug, determining drug exposure and dosing regimens. The prediction of hepatic clearance has remained a challenging task, especially for lipophilic and/or highly plasma protein bound compounds when using IVIVE approaches. Recent literature information indicated that protein-mediated effects may enhance compound uptake permeability, potentially accounting for the underestimation of the in vivo clearance by in vitro data. In this project, the uptake of a set of highly protein bound compounds that are OATP1B1 and non-OATP1B1 substrates was studied in the presence and absence of plasma proteins using two cellular models: plated primary human hepatocytes (PHH) and OATP1B1-transfected HEK293 cells. Potential protein-mediated effects were observed affecting passive permeability and active transport as well. Scaling factors (SF) for active uptake (PSinf,act) were established in order to improve IVIVE when using plated PHH incubated with buffer or serum as in vitro system, however, it was not possible to establish the corresponding SF for experiments with OATP-expressing HEK293 cells. Finally, a novel fitting model to improve the accuracy of the uptake assay data was tested.<br /><br />
000145999 521__ $$aMáster Universitario en Biofísica y Biotecnología Cuantitativa / Master in Biophysics and Quantitative Biotechnology
000145999 540__ $$aDerechos regulados por licencia Creative Commons
000145999 700__ $$aHuth, Felix$$edir.
000145999 700__ $$aAbián Franco, Olga$$edir.
000145999 7102_ $$aUniversidad de Zaragoza$$bBioquímica y Biología Molecular y Celular$$cBioquímica y Biología Molecular
000145999 8560_ $$f756430@unizar.es
000145999 8564_ $$s5240335$$uhttps://zaguan.unizar.es/record/145999/files/TAZ-TFM-2023-378.pdf$$yMemoria (eng)
000145999 909CO $$ooai:zaguan.unizar.es:145999$$pdriver$$ptrabajos-fin-master
000145999 950__ $$a
000145999 951__ $$adeposita:2024-11-22
000145999 980__ $$aTAZ$$bTFM$$cCIEN
000145999 999__ $$a20230612101343.CREATION_DATE