PET imaging to assess the impact of P-glycoprotein on pulmonary drug delivery in rats
2022
Hernández-Lozano, Irene | Mairinger, Severin | Filip, Thomas | Sauberer, Michael | Wanek, Thomas | Stanek, Johann | Sake, Johannes A. | Pekar, Thomas | Ehrhardt, Carsten | Langer, Oliver
Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[¹¹C]verapamil ([¹¹C]VPM) and [¹¹C]-N-desmethyl-loperamide ([¹¹C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b⁽⁻/⁻⁾ and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUCₗᵤₙg_ᵣᵢgₕₜ) to [¹¹C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b⁽⁻/⁻⁾ rats, respectively, compared to untreated wild-type rats. For [¹¹C]dLOP, AUCₗᵤₙg_ᵣᵢgₕₜ was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b⁽⁻/⁻⁾ rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans.
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