Descripción del proyecto
Vesículas extracelulares que predicen la respuesta y eliminación de fármacos
La absorción, distribución, metabolismo y eliminación de los fármacos están mediados por transportadores de fármacos transmembranarios específicos. La expresión del transportador varía mucho entre las personas, así como entre los diferentes tejidos en la misma persona y puede dar lugar a distintas concentraciones de fármacos en el plasma y efectos adversos graves. No existe una manera fácil de determinar la expresión de los transportadores de fármacos; para ello, en el proyecto EVPERS, financiado con fondos europeos, se propone utilizar vesículas extracelulares en sangre y orina. La correlación de los niveles del transportador en las vesículas extracelulares con los del tejido nativo validará el método y ayudará a predecir la farmacocinética del fármaco de una manera no invasiva.
Objetivo
Drug transporters of the ATP-binding cassette (ABC) family (e.g. P-gp, MRP2 and BCRP) promote the intestinal, biliary and urinary excretion of a wide range of drugs and, thus, determine their bioavailability, therapeutic efficacy and toxicity. Transporter expression is highly variable between individuals and within the same individual. This may result in enormous differences in the plasma concentration of a drug, which for drugs with a narrow therapeutic index may result in life-threatening situations. Extraction of biopsies would be the only option to measure transporter expression in tissues and adapt the therapeutic strategy. However, this is not performed due to its invasive character. Extracellular vesicles (EVs) are nanoparticles released by all cells of the organism. Their cargo (proteins, RNA and lipids) is frequently a dynamic fingerprint of the cell. The presence of EVs from different tissues in blood and urine allows for an easy access. The aim of this project is to evaluate if the amount of ABC transporters in EVs from blood and urine can be used to specifically predict the transporter expression at the tissues of origin under basal and induced conditions, as well as to predict in vivo drug pharmacokinetics. Following work packages (WP) are proposed: WP I: EVs as dynamic surrogate for ABC expression in vitro and ex vivo. I.I. Validation of an analytical protocol for the quantification of ABC transporters in EVs, I.II. Correlation between ABC expression in biopsies and in EVs from the same specimens, I.III. Correlation between expression of ABCs in EVs from primary cells and the expression and activity of ABCs in the cells of origin under basal and induced conditions. WP II: EVs as biomarker for drug pharmacokinetics. II.I. Optimization of the immunopurification of circulating hepatic-, intestinal- and renal EVs, II.II. Correlation of ABC transporter expression in EVs with the pharmacokinetics of an ABC model substrate under basal and induced conditions.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
69120 Heidelberg
Alemania