title: Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).
abstract: OBJECTIVE
  The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009).
  
  
  METHODS
  BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV.
  
  
  RESULTS
  A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study.
  
  
  CONCLUSIONS
  A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. pgershko@interchange.ubc.ca
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.forename: Olena
authors.initials: O
authors.lastname: Sivak
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Wasan
authors.forename: Alex B
authors.initials: AB
authors.lastname: Magil
authors.forename: David
authors.initials: D
authors.lastname: Owen
authors.forename: John G
authors.initials: JG
authors.lastname: Clement
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B