title: Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, moxifloxacin, and grepafloxacin.
abstract: The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF, and 19.1 ± 10.5 for GRX (means ± standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (VELF), passive diffusion clearance (QELF), and active efflux clearance (CLout) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
authors.forename: Aline Vidal Lacerda
authors.initials: AV
authors.lastname: Gontijo
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Brillault
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grégoire
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamarche
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Service de Toxicologie-Pharmacocinétique, CHU de Poitiers, Poitiers, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Gobin
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Service de Toxicologie-Pharmacocinétique, CHU de Poitiers, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France william.couet@univ-poitiers.fr.
authors.forename: William
authors.initials: W
authors.lastname: Couet
authors.affiliation: Inserm U1070, Pôle Biologie Santé, Poitiers, France Service de Toxicologie-Pharmacocinétique, CHU de Poitiers, Poitiers, France Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchand
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001702:Biopharmaceutics; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D000077266:Moxifloxacin; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000032:analysis
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D010879:Piperazines; D002939:Ciprofloxacin; D014508:Urea; C075375:grepafloxacin; D000077266:Moxifloxacin