Effect of budesonide on pulmonary activity of multidrug resistance-associated protein 1 assessed with PET imaging in rats

by Selleckchem | Oct 23 2023

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a highly abundant efflux transporter in the lungs, which protects cells from toxins and oxidative stress and has been implicated in the pathophysiology of chronic obstructive pulmonary disease and cystic fibrosis. There is evidence from in vitro studies that the inhaled glucocorticoid budesonide can inhibit MRP1 activity. We used positron emission tomography (PET) imaging with 6-bromo-7-[11C]methylpurine ([11C]BMP), which is transformed in vivo into a radiolabeled MRP1 substrate, to assess whether intratracheally (i.t.) aerosolized budesonide affects pulmonary MRP1 activity in rats. Three groups of rats (n = 5-6 each) underwent dynamic PET scans of the lungs after i.t. aerosolization of either [11C]BMP alone, or [11C]BMP mixed with either budesonide (0.04 mg, corresponding to the maximum soluble dose) or the model MRP1 inhibitor MK571 (2 mg). From PET-measured radioactivity concentration-time curves, the rate constant describing radioactivity elimination from the right lung (kE,lung) and the area under the curve (AUClung) were calculated from 0 to 5 min after start of the PET scan as measures of pulmonary MRP1 activity. Co-administration of MK571 resulted in a pronounced decrease in kE,lung (25-fold, p < 0.0001) and an increase in AUClung (5.3-fold, p < 0.0001) when compared with vehicle-treated animals. In contrast, in budesonide-treated animals kE,lung and AUClung were not significantly different from the vehicle group. Our results show that i.t. aerosolized budesonide at an approximately 5 times higher dose than the maximum clinical dose leads to no change in pulmonary MRP1 activity, suggesting a lack of an effect of inhaled budesonide treatment on the MRP1-mediated cellular detoxifying capacity of the lungs. However, the strong effect observed for MK571 raises the possibility for the occurrence of transporter-mediated drug-drug interactions at the pulmonary epithelium with inhaled medicines.

Comments:

The study you described investigated the effect of intratracheally (i.t.) aerosolized budesonide, a glucocorticoid, on the activity of the multidrug resistance-associated protein 1 (MRP1/ABCC1) in the lungs of rats. MRP1 is an efflux transporter that plays a role in protecting cells from toxins and oxidative stress and has been implicated in the development of chronic obstructive pulmonary disease (COPD) and cystic fibrosis.

The researchers used positron emission tomography (PET) imaging with a radiolabeled MRP1 substrate called 6-bromo-7-[11C]methylpurine ([11C]BMP) to assess the pulmonary MRP1 activity in rats. Three groups of rats were studied: one group received only [11C]BMP aerosol, another group received [11C]BMP mixed with budesonide, and the third group received [11C]BMP mixed with a model MRP1 inhibitor called MK571.

The researchers measured the rate constant describing radioactivity elimination from the right lung (kE,lung) and the area under the curve (AUClung) from the PET scans as indicators of pulmonary MRP1 activity. The results showed that co-administration of MK571 significantly decreased kE,lung (25-fold decrease) and increased AUClung (5.3-fold increase) compared to the group treated with the vehicle (no treatment). This suggests that MK571 strongly inhibited MRP1 activity in the lungs.

On the other hand, the group treated with budesonide did not show significant differences in kE,lung and AUClung compared to the vehicle group. This indicates that the aerosolized budesonide, even at a dose approximately five times higher than the maximum clinical dose, did not affect pulmonary MRP1 activity in the rats. Therefore, the study suggests that inhaled budesonide treatment does not impact the MRP1-mediated detoxifying capacity of the lungs.

However, the significant effect observed with MK571 raises the possibility of transporter-mediated drug-drug interactions at the pulmonary epithelium when using inhaled medications. This implies that certain drugs or substances may interact with MRP1 and potentially affect its activity in the lungs, leading to altered drug disposition or efficacy.

It is important to note that this study was conducted in rats, and further research is necessary to confirm these findings in humans and explore the potential implications for drug-drug interactions in clinical settings.