Article

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

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (impact factor: 3.15). 02/2012; 81(1):142-8. DOI:10.1016/j.ejpb.2012.02.003 pp.142-8
Source: PubMed

ABSTRACT 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.

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Keywords

50% reduction
 
5mg/kg intravenously
 
accentuated toxicity
 
analogue valspodar
 
Co-administration
 
co-solvent evaporation method
 
commercially available DOX
 
conventional Cremophor EL-based formulation
 
Cyclosporine
 
DOX clearance
 
doxorubicin
 
greater
 
P-gp inhibitors
 
polymeric micellar formulation
 
polymeric micelles
 
Sandimmune®
 
single dose
 
single intravenous dose
 
Sprague-Dawley rats
 
valspodar