title: Aerosol therapy with colistin methanesulfonate: a biopharmaceutical issue illustrated in rats.
abstract: The aim of this study was to evaluate the biopharmaceutical behavior of colistin methanesulfonate (CMS) with special focus on colistin presystemic formation after CMS nebulization in rats. CMS was administered (15 mg x kg(-1) of body weight) either intravenously for systemic pharmacokinetic studies (n = 6) or as an intratracheal nebulization for systemic pharmacokinetic studies (n = 5) or for CMS and colistin concentration measurements in epithelial lining fluid (ELF) at 30, 120, and 240 min after nebulization (n = 14). CMS and colistin concentrations were determined by a new liquid chromatography (LC)-tandem mass spectrometry (MS/MS) assay. Pharmacokinetic parameters were estimated by noncompartmental analysis. CMS and colistin pharmacokinetic data were consistent with previously published values when comparisons were possible. The fraction of the CMS dose converted systematically into colistin after intravenous CMS administration was estimated to be 12.5% on average. After CMS nebulization it was estimated that about two-thirds of the dose was directly absorbed within the systemic circulation, whereas one-third was first converted into active colistin, which was eventually absorbed. As a consequence, the colistin area under curve (AUC) reflecting systemic availability was about 4-fold greater after CMS intratracheal nebulization (607 +/- 240 microg x min x ml(-1)) than after CMS intravenous administration (160 +/- 20 microg x min x ml(-1)). CMS concentrations in ELF at 30 min and 120 min postnebulization were very high (in the order of several mg/ml) due to the limited volume of ELF but were considerably reduced at 240 min. Although lower (15% +/- 5% at 120 min) in relative terms, colistin concentrations in ELF could be high enough for being active against microorganisms following CMS nebulization.
authors.affiliation: INSERM ERI-23, 40 Avenue du Recteur Pineau, 86000 Poitiers, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchand
authors.forename: Patrice
authors.initials: P
authors.lastname: Gobin
authors.forename: Julien
authors.initials: J
authors.lastname: Brillault
authors.forename: Sara
authors.initials: S
authors.lastname: Baptista
authors.forename: Christophe
authors.initials: C
authors.lastname: Adier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivier
authors.forename: Olivier
authors.initials: O
authors.lastname: Mimoz
authors.forename: William
authors.initials: W
authors.lastname: Couet
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D002460:Cell Line; D002853:Chromatography, Liquid; D003091:Colistin / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D003091:Colistin