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1. Toxicol Appl Pharmacol. 2012 Mar 23. [Epub ahead of print]

Oral and inhaled corticosteroids: Differences in P-glycoprotein (ABCB1) mediated
efflux.

Crowe A, Tan AM.

There is concern that P-glycoprotein mediated efflux contributes to steroid
resistance. Therefore, this study examined bidirectional corticosteroid transport
and induction capabilities for P-glycoprotein (P-gp) to understand which of the
systemic and inhaled corticosteroids interacted with P-gp to the greatest extent.
Hydrocortisone, prednisolone, prednisone, methylprednisolone, and dexamethasone
represented systemically active drugs, while fluticasone propionate,
beclomethasone dipropionate, ciclesonide and budesonide represented inhaled
corticosteroids. Aldosterone and fludrocortisone represented mineralocorticoids.
All drugs were detected using individually optimised HPLC protocols. Transport
studies were conducted through Caco-2 monolayers. Hydrocortisone and aldosterone
had efflux ratios below 1.5, while prednisone showed a P-gp mediated efflux ratio
of only 1.8 compared to its active drug, prednisolone, with an efflux ratio of
4.5. Dexamethasone and beclomethasone had efflux ratios of 2.1 and 3.3
respectively, while this increased to 5.1 for methylprednisolone. Fluticasone
showed an efflux ratio of 2.3. Protein expression studies suggested that all of
the inhaled corticosteroids were able to induce P-gp expression, from 1.6 to 2
times control levels. Most of the systemic corticosteroids had higher passive
permeability (>20×10(-6)cm/s) compared to the inhaled corticosteroids
(>5×10(-6)cm/s), except for budesonide, with permeability similar to the systemic
corticosteroids. Inhaled corticosteroids are not transported by P-gp to the same
extent as systemic corticosteroids. However, they are able to induce P-gp
production. Thus, inhaled corticosteroids may have greater interactions with
other P-gp substrates, but P-gp itself is less likely to influence resistance to
the drugs.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22464980 [PubMed - as supplied by publisher]