Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands
Issue Date
2001Author
Hamilton, Karen O.
Yazdanian, Mehran
Audus, Kenneth L.
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Metadata
Show full item recordAbstract
The purpose of this work was to investigate if P-glycoprotein (Pgp) efflux pump activity could be inhibited in the sub-bronchial epithelial cell line, Calu-3, by glucocorticosteroids and β-ligands. The Pgp modulation efficiency of each compound was determined by its ability to increase the accumulation of the Pgp substrate rhodamine 123 (Rh123) accumulation in these cells. Pgp inhibition was observed at ≥ 100 μM steroids and β-ligand. The modulation effectiveness of the β-ligands increased with increasing hydrophobicity (log Poctanol/aqueous) whereas an obvious correlation was not obtained with the complete set of steroids tested. Steroidal Pgp substrates did not affect Rh123 accumulation (e.g., aldosterone, dexamethasone, 11β, 17α, 21-OH progesterone). In contrast, two hydrophobic non P-gp steroidal substrates (testosterone and progesterone) displayed different effects on Rh123 accumulation, with progesterone being the more potent modulator. The most hydrophobic β-ligand, propranolol, a known Pgp substrate, gave the largest increase in Rh123 accumulation in this therapeutic class. The β-ligand modulation efficiency could also be correlated to Pgp structural recognition elements such as hydrogen bonding potential, the presence of a basic nitrogen and planar aromatic ring. No effect on Rh123 accumulation was observed with the formulation additives tested (ethanol, glycerol and palmitoyl carnitine) at concentrations previously reported to be non-toxic to Calu-3 cells.
Description
Please note that this is an author-produced PDF of an article accepted for publication following peer review. The publisher version is available on its site.
Collections
- Pharmacy Scholarly Works [286]
Citation
Hamilton, K.O., Yazdanian, M., and Audus, K.L. (2001) Modulation of P-glycoprotein activity in Calu-3 cells using steroids and b-ligands. Int. J. Pharm. 228, 171-179. PMID: 11576779 http://dx.doi.org/10.1016/S0378-5173(01)00836-5
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