Description du projet
Des vésicules extracellulaires pour prédire la réponse et la clairance des médicaments
L’absorption, la distribution, le métabolisme et l’élimination des médicaments sont régis par des transporteurs transmembranaires spécifiques. L’expression des transporteurs varie fortement d’un individu à l’autre ainsi qu’entre les différents tissus d’un même individu, ce qui peut entraîner des concentrations différentes de médicaments dans le plasma et de graves effets indésirables. Il n’existe aucune méthode simple permettant de déterminer l’expression des transporteurs de médicaments. Pour y parvenir, le projet EVPERS, financé par l’UE, propose d’utiliser les vésicules extracellulaires du sang et de l’urine. La corrélation des niveaux de transporteurs dans les vésicules extracellulaires avec ceux des tissus natifs validera l’approche et aidera à prédire la pharmacocinétique des médicaments de manière non invasive.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
69120 Heidelberg
Allemagne