title: Pharmacokinetics and Biodistribution of GDC-0449 Loaded Micelles in Normal and Liver Fibrotic Mice.
abstract: To determine the pharmacokinetic parameters and biodistribution of GDC-0449 loaded polymeric micelles after systemic administration into common bile duct ligation (CBDL) induced liver fibrotic mice.
  
  
  
  We used GDC-0449 encapsulated methoxy poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (PEG-PCD) non-targeted polymeric micelles for GDC-0449 delivery to normal and liver fibrotic mice. To maximize GDC-0449 delivery to hepatic stellate cells (HSCs), mixed micelles formulations with 10, 20 and 30% w/w mannose-6-phosphate (M6P)-conjugated micelles were administered to normal and liver fibrotic mice for targeting M6P/IGF-IIR overexpressed on activated HSCs and biodistribution of GDC-0449 was determined at 30 and 120 min post systemic administration.
  
  
  
  GDC-0449 distributed to all major organs after systemic administration of drug loaded micelles, with higher accumulation in the liver of both normal and fibrotic mice. The plasma concentration versus time profiles suggest rapid clearance of GDC-0449 after systemic administration of drug loaded micelles in both normal and fibrotic mice, with similar plasma clearance (CL), area under the curve (AUCint) and volume of distribution at steady state (Vss). However, there is significant increase in GDC-0449 accumulation in the liver when M6P-conjugated mixed micelles were injected, with the highest GDC-0449 concentration in the liver with mixed micelles carrying 30% M6P-conjugated polymer. HSCs accounted for 14.19% of GDC-0449 accumulation for M6P-targeted micelles in fibrotic mice compared to 5.62% of non-targeted micelles in the liver uptake study.
  
  
  
  M6P-conjugated GDC-0449 loaded mixed micelles may be used as a potential drug delivery vehicle for treating liver fibrosis.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Rinku
authors.initials: R
authors.lastname: Dutta
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Virender
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Medicine, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Ruby E
authors.initials: RE
authors.lastname: Evande
authors.affiliation: Department of Medicine, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center (UNMC), 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA. ram.mahato@unmc.edu.
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D065546:Drug Liberation; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008360:Mannosephosphates / Q000737:chemistry; D008810:Mice, Inbred C57BL; D008823:Micelles; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013499:Surface Properties; D014018:Tissue Distribution
chemical_list: D000813:Anilides; D004337:Drug Carriers; C538724:HhAntag691; D008360:Mannosephosphates; D008823:Micelles; D011091:Polyesters; D011725:Pyridines; C556102:poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol); C027693:mannose-6-phosphate; D011092:Polyethylene Glycols
keywords: GDC-0449; biodistribution; liver fibrosis; micelles