title: Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B.
abstract: OBJECTIVE
  We hypothesized that effective prophylactic treatment of fungal infections would require adequate drug penetration and retention at potential infection sites. Using a mouse model, we examined liposomal amphotericin B (L-AmB) biodistribution, cell localization and retention in kidneys, lungs, liver and spleen to evaluate effective dosing regimens for prophylaxis of Candida glabrata and Candida albicans infections.
  
  
  METHODS
  Following treatment of mice with cumulative doses of L-AmB (60-225 mg/kg), a bioassay was done to determine tissue drug concentrations 12 h to 6 weeks post-treatment. Immunohistochemical staining with anti-amphotericin B antibodies was used for cellular drug localization. Mice were treated prophylactically with 15-90 mg/kg L-AmB and challenged intravenously 1-7 days later with C. glabrata or they were given a total of 60 mg/kg as daily or intermittent dosing followed by intravenous challenge with C. albicans 3 or 6 weeks later.
  
  
  RESULTS
  On the basis of microg/g tissue, the relative amount of drug was in the order spleen > liver > kidneys > lungs. Amphotericin B levels were maintained above the MIC for many fungi for 1 week in lungs and for as long as 6 weeks in kidneys and spleen. Drug localized in kidney tubular epithelial cells and in macrophages of liver and spleen. In prophylactic models, fungal burden was reduced by several 1000-fold or was undetectable within target tissues (kidneys, spleen).
  
  
  CONCLUSIONS
  These observations underscore the importance of including drug tissue levels to obtain a better understanding of L-AmB efficacy. The sustained concentrations of bioactive AmB in many tissues provide a further rationale for investigating L-AmB prophylactic regimens.
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, CA 91768, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Jon A
authors.initials: JA
authors.lastname: Olson
authors.forename: David
authors.initials: D
authors.lastname: Constable
authors.forename: Julie
authors.initials: J
authors.lastname: Schwartz
authors.forename: Richard T
authors.initials: RT
authors.lastname: Proffitt
authors.forename: Jill P
authors.initials: JP
authors.lastname: Adler-Moore
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects*; D041221:Candida glabrata / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000517:prevention & control*; D005260:Female; D007668:Kidney / Q000187:drug effects; D008081:Liposomes; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000666:Amphotericin B