Impacto de la unión a proteínas en la captación hepática y en la extrapolación in vitro - in vivo de la eliminación

García Gadea, Sara
Huth, Felix (dir.) ; Abián Franco, Olga (dir.)

Universidad de Zaragoza, CIEN, 2023
Departamento de Bioquímica y Biología Molecular y Celular, Área de Bioquímica y Biología Molecular

Máster Universitario en Biofísica y Biotecnología Cuantitativa / Master in Biophysics and Quantitative Biotechnology

Resumen: Drug 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.

Tipo de Trabajo Académico: Trabajo Fin de Master