title: Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats.
abstract: OBJECTIVE
  To determine the pharmacokinetics and efficacy of tobramycin against pulmonary infections of Pseudomonas aeruginosa in rats after intratracheal administration of conventional and liposomal formulations.
  
  
  METHODS
  Male Sprague-Dawley rats were inoculated with 10(6) cfu of a mucoid variant of P. aeruginosa (MIC of tobramycin for PA 508 = 1 mg/l) and tobramycin (conventional or liposomal formulations) was administered in single (490 microg) and multiple dose (490 microg during 4 days) experiments. Rats were killed at multiple time points to determine the residual cfu of P. aeruginosa and tobramycin amounts in lungs. Pharmacokinetic parameters were calculated using a two-compartment model with NONMEM.
  
  
  RESULTS
  Mean (+/-S.D.) elimination half-life (t(1/2beta)) and pulmonary exposure (AUC) of the conventional formulation were 14.0 +/-4.0 h and 663 +/-89 microg x h/lungs, respectively. The pharmacokinetic profile of liposomal tobramycin was markedly different, with a longer t(1/2beta) (34.4 +/-5 h, P < 0.05), resulting in an increased AUC (3890 +/-560 microg x h/lungs, P < 0.05). chi(2) analyses were carried out on cfu data distributed in the following categories: below 10(3), 10(3)-10(5), and above 10(5) cfu. In the single dose experiments, approximately 90% of the observations were above 10(5) cfu for both formulations. Significant differences in cfu distribution were observed after multiple treatments, with approximately 10% of the observations falling below 10(3) cfu of P. aeruginosa for the conventional formulation versus 30% for the liposomal formulation.
  
  
  CONCLUSIONS
  The liposomal formulation of tobramycin promoted drug retention in lungs and improved its efficacy after multiple treatments.
authors.affiliation: Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.forename: J L
authors.initials: JL
authors.lastname: Brazier
authors.forename: J
authors.initials: J
authors.lastname: Lavigne
authors.forename: M P
authors.initials: MP
authors.lastname: Ducharme
mesh_terms: D000818:Animals; D007278:Injections, Spinal; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D008081:Liposomes; D014031:Tobramycin