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Expressions of multidrug resistance protein 1 ( MDR1 ) and multidrug resistance-associated protein 1 ( MRP1 ) in lung dendritic cells (LDCs) from young and aged mice. Flow cytometric analyses of MDR1 and MRP1 proteins in LDCs from young and aged mice were undertaken using C219 and MRPr1 monoclonal antibodies (fi lled profi les), respectively, or their isotype-matched control monoclonal antibodies (open profi les). The numbers shown in the top right-hand corners are the mean fl uorescence intensities determined by subtracting the mean fl uorescence of the C219 or anti-MRP1 monoclonal antibody from that of their isotype-matched antibody. The results shown are representative of three independent experiments.
Source publication
Multidrug resistance protein 1 and multidrug resistance–associated protein 1 are transporters that efflux diverse xenobiotics
from cells. We investigated changes in the expression and activity of multidrug resistance protein 1 and multidrug resistance–associated
protein 1 in highly purified lung dendritic cells (LDCs) during aging using magnetic an...
Context in source publication
Context 1
... and MRP1 protein expressions were examined by immunolabeling. MDR1 and MRP1 were clearly detected in LDCs from aged mice using C219 and MRPr1 antibodies, respectively, and the MFIs of C219 and MRPr1 monoclonal antibodies were increased compared with those of their isotype-matched control monoclonal antibodies ( Figure 1 ). There was no differ- ence in MFIs between LDCs from aged and young mice. ...
Citations
... [11] Protein detected by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) in whole lung and alveolar tissue but absent in bronchial samples (0.393 ± 0.172). [13] Slightly higher expressed in bronchial mucosa of smokers compared to nonsmokers, although no statistical significance due to highinterindividual variations [9] Mouse, rat, and hamster lung tissue and primary cells mRNA and protein present in various lung tissues and primary cells, [8,[14][15][16][17][18] rat mdr1a higher expressed than mrd1b in whole lung and alveolar type 1 (AT1) cells, while absent in alveolar type 2 (AT2) cells, [12,15] in mice whole-lung samples mrd1a is the only expressed variant. [16] Increasing expression intensity during culture time in rat primary alveolar cells [19] Primary cells AT1-like mRNA expressed at low levels [20] mostly localized to the surface of AT1 pneumocytes [12] AT2 mRNA expression moderate [20] HBEC mRNA expressed at low [20,21] or moderate levels, [22] mRNA and protein absent [23,24] or highinterindividual variation in expression shown [19] HPAEpiCs ...
Introduction:
Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. Areas covered: In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Expert opinion: Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.
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.
