title: 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. zbinkhathlan@ksu.edu.sa
authors.forename: Ziyad
authors.initials: Z
authors.lastname: Binkhathlan
authors.forename: Anooshirvan
authors.initials: A
authors.lastname: Shayeganpour
authors.forename: Dion R
authors.initials: DR
authors.lastname: Brocks
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology; D003524:Cyclosporins / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000633:toxicity; D004347:Drug Interactions; D007275:Injections, Intravenous; D007783:Lactones / Q000737:chemistry; D008297:Male; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D007783:Lactones; D008823:Micelles; D012997:Solvents; C473831:poly(ethylene oxide)-b-poly(caprolactone); D011092:Polyethylene Glycols; D004317:Doxorubicin; D016572:Cyclosporine; C070272:valspodar