Encapsulation of P-glycoprotein inhibitors by polymeric micelles can reduce their pharmacokinetic interactions with doxorubicin.
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.
Article: P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives.[show abstract] [hide abstract]
ABSTRACT: One of the major causes of failure in cancer chemotherapy is multidrug resistance (MDR), where cancer cells simultaneously become resistant to different anticancer drugs. Over-expression of membrane efflux pumps like P-glycoprotein (P-gp) that recognizes different chemotherapeutic agents and transports them out of the cell, plays a major role in MDR. The shortcoming of P-gp inhibitors in clinic has been attributed to their non-specific action on P-gp and/or non-selective distribution to non-target organs that leads to intolerable side effects by the P-gp inhibitor at doses required for P-gp inhibition upon systemic administration. Another major issue is the reduced elimination of P-gp substrates (e.g. anticancer drugs) and intolerable toxicities by anticancer drugs when co-administered with P-gp inhibitors. To overcome these shortcomings, new generation of P-gp inhibitors with improved specificity for P-gp have been developed. More recently, attention has been paid to the use of drug delivery systems primarily to restrict P-gp inhibition to tumor and reduce the non-selective inhibition of P-gp in non-target organs. This review will provide an overview and update on the status of P-gp inhibition approaches and the role of drug delivery systems in overcoming P-gp mediated MDR.Current cancer drug targets 01/2013; · 5.13 Impact Factor