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

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 5 mg/kg intravenously to Sprague–Dawley rats either alone or 30 min following a single intravenous dose (10 mg/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.

Graphical abstractPlasma concentration versus time profiles of doxorubicin (DOX) (5 mg/kg) in rat, either alone or 30 min following an intravenous dose (10 mg/kg) of (A) cyclosporine (CyA) or (B) valspodar.Figure optionsDownload full-size imageDownload high-quality image (150 K)Download as PowerPoint slide