title: Pharmacokinetics and in vivo efficacy of optimized oncocin derivatives.
abstract: OBJECTIVE
  To evaluate the efficacy of antimicrobial peptide Onc112 in a lethal Escherichia coli infection model and the pharmacokinetics of Onc72 and Onc112 administered intravenously or intraperitoneally in mice.
  
  
  METHODS
  Onc72, Onc112 and their major metabolites in blood, kidneys, liver, brain and urine were quantified by MS using multiple reaction monitoring (MRM) and isotope-labelled peptides.
  
  
  RESULTS
  Onc112 rescued all animals when administered intraperitoneally at a dose of 2.5 mg/kg and was thus slightly more efficient than Onc72. The MRM method provided limits of quantification in plasma, urine and kidney, liver and brain homogenates of 7-80 μg/L, well below the MICs of 2-4 mg/L. Onc72 and Onc112 reached all organs within 10 min when administered intraperitoneally (5 mg/kg). Their initial concentrations in plasma were 11.9 and 22.6 mg/L, respectively, with elimination t1/2 values of ∼14 and 21 min. The peptide concentrations in blood remained above their MICs for 20 min for Onc72 and 80 min for Onc112. The highest peptide concentrations were detected in kidney homogenates, which also contained the highest content of metabolites, indicating, together with the results from analysis of urine samples, that both peptides are cleared through the kidneys.
  
  
  CONCLUSIONS
  Onc72 and Onc112 reach organs, including the brain, within 10 min after intravenous and intraperitoneal administration. Onc112 remained in blood at concentrations above its MIC for 80 min. The pharmacokinetic profiles explain the high in vivo efficacies in models of systemic infection and indicate the potential use of these agents for the treatment of urinary tract infections.
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany.
authors.forename: Rico
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary Institute of Laboratory Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Ostorházi
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wende
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Knappe
authors.affiliation: Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany hoffmann@chemie.uni-leipzig.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D016903:Drug Monitoring; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C551620:oncocin