pgp - publications

Predict more pgp - ligand interactions now!

1. Eur J Pharm Biopharm. 2012 Feb 14. [Epub ahead of print]

Encapsulation of P-glycoprotein inhibitors by polymeric micelles can reduce their
pharmacokinetic interactions with doxorubicin.

Binkhathlan Z, Shayeganpour A, Brocks DR, Lavasanifar A.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Alberta,
Canada; Nanomedicine Research Unit, Department of Pharmaceutics, King Saud
University, Riyadh, Saudi Arabia.

Co-administration of P-glycoprotein (P-gp) inhibitors such as cyclosporine A
(CyA) and its analogue valspodar with doxorubicin (DOX) can result in diminished
clearance of DOX, leading to accentuated toxicity. The purpose of this study was
to evaluate whether the effect of these P-gp inhibitors on the pharmacokinetics
of DOX can be avoided through their encapsulation in polymeric micelles.
Cyclosporine A or valspodar was physically encapsulated in methoxypoly(ethylene
oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) micelles using co-solvent evaporation
method. The commercially available DOX was administered as a single dose of
5mg/kg intravenously to Sprague-Dawley rats either alone or 30min following a
single intravenous dose (10mg/kg) of either CyA or valspodar as part of
conventional or polymeric micellar formulation. Co-administration of DOX with
either Sandimmune® or valspodar in the conventional Cremophor EL-based
formulation was associated with greater than 50% reduction in DOX clearance (CL).
Although there was nearly 40% reduction in the CL of DOX with the polymeric
micellar formulation of CyA, there was only 6% reduction in CL of DOX upon
co-administration with the polymeric micellar formulation of valspodar. In
conclusion, encapsulation of cyclosporines, particularly valspodar, in polymeric
micelles was shown to reduce their effects on the pharmacokinetics of DOX in rat.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22361031 [PubMed - as supplied by publisher]