title: Antibacterial efficacy against an in vivo Salmonella typhimurium infection model and pharmacokinetics of a liposomal ciprofloxacin formulation.
abstract: The fluoroquinolone antibiotic ciprofloxacin has been encapsulated into large unilamellar vesicles (LUV) at efficiencies approaching 100%. Drug accumulation proceeded in response to a transmembrane gradient of methylammonium sulfate and occurred concomitantly with the efflux of methylamine. A mechanism for the encapsulation process is described. LUV composed of dipalmitoylphosphatidylcholine-cholesterol (DPPC/chol), distearoylphosphatidylcholine-cholesterol (DSPC/chol), or sphingomyelin-cholesterol (SM/chol) increased the circulation lifetime of ciprofloxacin after intravenous (i.v.) administration by > 15-fold. The retention of ciprofloxacin in liposomes in the circulation decreased in the sequence SM/chol > DSPC/chol > DPPC/chol. Increased circulation lifetimes were associated with enhanced delivery of the drug to the livers, spleens, kidneys, and lungs of mice. Encapsulation of ciprofloxacin also conferred significant increases in the longevity of the drug in the plasma after intraperitoneal administration and in the lungs after intratracheal administration in comparison to free ciprofloxacin. The efficacy of a single i.v. administration of an SM/chol formulation of ciprofloxacin was measured in a Salmonella typhimurium infection model. At 20 mg of ciprofloxacin per kg of body weight, the encapsulated formulation resulted in 10(3)- to 10(4)-fold fewer viable bacteria in the livers and spleens of infected mice than was observed for animals treated with free ciprofloxacin. These results show the utility of liposomal encapsulation of ciprofloxacin in improving the pharmacokinetics, biodistribution, and antibacterial efficacy of the antibiotic. In addition, these formulations are well suited for i.v., intraperitoneal, and intratracheal or aerosol administration.
authors.affiliation: Inex Pharmaceuticals Corporation, Burnaby, British Columbia, Canada. mwebb@inexpharm.com
authors.forename: M S
authors.initials: MS
authors.lastname: Webb
authors.forename: N L
authors.initials: NL
authors.lastname: Boman
authors.forename: D J
authors.initials: DJ
authors.lastname: Wiseman
authors.forename: D
authors.initials: D
authors.lastname: Saxon
authors.forename: K
authors.initials: K
authors.lastname: Sutton
authors.forename: K F
authors.initials: KF
authors.lastname: Wong
authors.forename: P
authors.initials: P
authors.lastname: Logan
authors.forename: M J
authors.initials: MJ
authors.lastname: Hope
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002214:Capsules; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005260:Female; D007274:Injections, Intraperitoneal; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012478:Salmonella Food Poisoning / Q000188:drug therapy*; D012486:Salmonella typhimurium / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects / Q000382:microbiology
chemical_list: D000890:Anti-Infective Agents; D002214:Capsules; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D002939:Ciprofloxacin