title: Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres.
abstract: A comparative pharmacokinetic study was conducted in rats after intratracheal aerosolization of levofloxacin, as a solution, as immediate-release chitosan microspheres or as sustained-release PLGA microspheres. A pharmacokinetic model was constructed to model levofloxacin concentrations both in plasma and in the lung epithelial lining fluid (ELF). The plasma and ELF experimental concentration profiles versus time were similar for the intravenous and intratracheal levofloxacin solutions and for the intratracheal levofloxacin-loaded chitosan microsphere dry powder, indicating that levofloxacin diffused almost instantaneously through the broncho-alveolar barrier and that the chitosan microspheres released levofloxacin very rapidly, as anticipated from in vitro release studies. The bioavailability for the intratracheal levofloxacin solution and intratracheal chitosan microspheres was estimated to be 98% and 71%, respectively, both with a direct release into the ELF compartment. The ELF-to-unbound plasma AUC ratios were slightly above 2 and may result from an efflux transport. For the intratracheal PLGA microspheres, a high ELF-to-unbound plasma AUC concentration ratio (311) was observed and high levofloxacin concentrations were maintained in ELF for at least 72h in consistency with the in vitro release studies. The bioavailability was 92%, with 19% of the dose released immediately (burst release) into the ELF and 73% released slowly into the ELF from a depot compartment, i.e. the PLGA microspheres, according to a Weibull model. These results highlight the benefit of using sustained-release microspheres administered as aerosols to provide and to maintain high pulmonary concentrations of an antibiotic characterized with a high permeability profile through the broncho-alveolar barrier. The sustained-release microsphere dry powder aerosol may therefore provide advantages over solutions or pure drug dry powders for inhalation in terms of treatment efficiency, ease of use and frequency of administration.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-548 Coimbra, Portugal; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France.
authors.forename: Marisa C
authors.initials: MC
authors.lastname: Gaspar
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grégoire
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-548 Coimbra, Portugal; Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
authors.forename: João J S
authors.initials: JJ
authors.lastname: Sousa
authors.affiliation: Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Alberto A C C
authors.initials: AA
authors.lastname: Pais
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamarche
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; CHU Poitiers, 2 rue de la Milétrie, 86000 Poitiers, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Gobin
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France. Electronic address: jean.christophe.olivier@univ-poitiers.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivier
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France; CHU Poitiers, 2 rue de la Milétrie, 86000 Poitiers, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchand
authors.affiliation: INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France; CHU Poitiers, 2 rue de la Milétrie, 86000 Poitiers, France.
authors.forename: William
authors.initials: W
authors.lastname: Couet
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019344:Lactic Acid / Q000737:chemistry*; D064704:Levofloxacin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D064704:Levofloxacin; D048271:Chitosan
keywords: Chitosan; Levofloxacin; Microsphere; PLGA; Pulmonary delivery; Pulmonary pharmacokinetics; Sustained release