Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing.
The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.
Aliabadi
Hamidreza Montazeri
HM
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada.
Elhasi
Sara
S
Brocks
Dion R
DR
Lavasanifar
Afsaneh
A
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008823:Micelles; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley