Influence of P-glycoprotein on pulmonary disposition of the model substrate [11C]metoclopramide assessed by PET imaging in rats
Severin Mairinger, Irene Hernández-Lozano, Thomas Filip, Mathilde Löbsch, Johann Stanek, Markus Zeitlinger, Marcus Hacker, Nicolas Tournier, Thomas Wanek, Carsten Ehrhardt, Oliver Langer
Abstract
In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the intrapulmonary pharmacokinetics of the intratracheally (i.t.) aerosolized model P-gp substrate [11C]metoclopramide in presence and absence of P-gp activity by means of positron emission tomography (PET) imaging in rats. Data were compared to data previously acquired with the model P-gp substrates (R)-[11C]verapamil and [11C]N-desmethyl-loperamide, using the same experimental set-up. Groups of wild-type rats, either untreated or treated with the P-gp inhibitor tariquidar, and Abcb1a/b(-/-) rats underwent 90-min dynamic PET scans after i.t. aerosolization of [11C]metoclopramide. Lung exposure to [11C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUClung). AUClung values were significantly higher in Abcb1a/b(-/-) rats (1.8-fold, p ≤ 0.0001) and in tariquidar-treated wild-type rats (1.6-fold, p ≤ 0.01) than in untreated wild-type rats. This differed from previously obtained results with (R)-[11C]verapamil and [11C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [11C]metoclopramide was not or only to a small extent affected by P-gp activity, presumably due to the compound's high passive permeability. The increased lung retention of [11C]metoclopramide may be due to decreased P-gp-mediated clearance into the blood in absence of P-gp activity in capillary endothelial cells. The overall effect of P-gp on the lung exposure to inhaled P-gp substrate drugs may, thus, be determined by a balance of opposing effects at the pulmonary epithelium and endothelium.