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Imagerie translationnelle pour la mise en évidence des répercussions pharmacocinétiques des transporteurs de médicaments

Abstract : Drug distribution from blood to tissues, where pharmacological and/or toxic effects occur, often involves transporters that control their passage across biological membranes. Organic-Anion Transporting Polypeptides (OATP), among other hepatocyte transporters, mediate the hepatic elimination of many drugs. Some OATPs are expressed in other organs where their impact for pharmacokinetics is unclear.The aim of this work was to develop original imaging methods to selectively measure the OATP-mediated transport at the blood-tissue interface. First, we used [99mTc]mebrofenin, a radiopharmaceutical routinely used for hepatobiliary scintigraphy. In rats, we validated a targeted pharmacological inhibition protocol, feasible in Humans, allowing to study the sinusoidal OATP activity apart from biliary excretion,in a non-invasive way.Then we optimized the analysis methods of PET (positron emission tomography) kinetics obtained using the new OATP-substrate probe [11C]glyburide, used for the first time in Humans. A whole-body dynamic acquisition method enabled quantitative determination of OATP function in the liver and other tissues in primate and in Humans.Translational imaging offers novel perspectives for original pharmacokinetic studies, that could not be envisioned in humans so far. Thanks to the development of radiopharmaceuticals to measure drug transporters activity and to the optimization of imaging data analysis, it is possible to study their functional impact on drug distribution and elimination at the tissue level in humans.
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Submitted on : Monday, February 22, 2021 - 3:22:29 PM
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Solène Marie. Imagerie translationnelle pour la mise en évidence des répercussions pharmacocinétiques des transporteurs de médicaments. Pharmacologie. Université Paris-Saclay, 2020. Français. ⟨NNT : 2020UPASQ004⟩. ⟨tel-03148829⟩

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