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Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux

Abstract : In the face of the shortage of new anti-infectives and the ever-increasing emergence of multi-resistant infectious agents, it is essential to make better use of the therapeutic arsenal at our disposal. This may involve the use of new routes of administration in order to act more effectively locally. To treat lung infections, inhalation or nebulisation appear to be a good option. It has been shown previously that rather hydrophilic molecules were good candidates for this route of administration because the pulmonary epithelium was not very permeable to them and that the active drug was sequestered in the lung. On the other hand, for lipophilic compounds that diffuse rapidly through the epithelium, pulmonary administration is of little therapeutic interest. The situation becomes more complex in the case of prodrug nebulization and/or when efflux pumps are involved in the pulmonary distribution of anti-infectives. In order to better characterize the role of efflux pumps in the pulmonary distribution of anti-infectives in vitro and their impact in vivo, the pulmonary distribution of several anti-infectives was evaluated according to a standardized protocol in rats, allowing measurement and comparison of free plasma and pulmonary epithelial fluid (ELF) concentrations after systemic and intratracheal administration. The first study focuses on the pulmonary distribution of oseltamivir, an anti-viral active against influenza, which is administered as a prodrug (oseltamivir phosphate (OP)). It has been shown in vitro that OP (non-active) is a substrate for efflux pumps and that this active transport is characterized in vivo by higher local concentrations of OP in ELF than in plasma regardless of the route of administration (intravenous or nebulization). However, these high pulmonary prodrug concentrations have little effect on pulmonary concentrations of the active molecule (oseltamivir carboxylate (OC)), due to low local conversion to the active compound and pulmonary permeability of the OC. The second study presents the case of oxazolidinones (linezolide and tedizolide) used to treat Gram-positive infections for which in vivo studies in humans had previously shown local concentrations (ELF) higher than plasma concentrations after oral administration. These data were found in rats according to our standardized protocol and supplemented with post-nebulization data, suggesting a major role for transporters in the pulmonary diffusion of tedizolide. However, membrane permeability and in vitro inhibition studies conducted in a cellular model (NCI-H441) were unable to demonstrate the role of these efflux transporters on high pulmonary concentrations. Other explanations have been considered such as protein binding in ELF or intracellular penetration of active compound. In conclusion, these in vivo and in vitro studies on 4 active compounds have allowed us to improve our knowledge of the parameters that govern the pulmonary diffusion of anti-infectives such as permeability and affinity for efflux transporters and to show the complexity of extrapolation in vitro/in vivo.
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Submitted on : Thursday, April 2, 2020 - 10:23:10 AM
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  • HAL Id : tel-02529114, version 1



Romain Carrez. Implication in vivo des transporteurs pulmonaires sur la pharmacocinétique des anti-infectueux. Pneumologie et système respiratoire. Université de Poitiers, 2019. Français. ⟨NNT : 2019POIT1803⟩. ⟨tel-02529114⟩



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