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.

FIG. 1.

Representation of CMS behavior after intratracheal nebulization. A fraction of the CMS dose is absorbed systematically (F_CMS,lung), which is then partially converted into colistin within the systemic circulation (f_m,syst). Another fraction of the CMS dose is converted into colistin presystematically (f_m,lung), which is then partially absorbed within the systemic circulation (F_coli,lung).

FIG. 2.

Mean total plasma concentration-versus-time profiles (±SD) for CMS and/or colistin after i.v. administration of CMS (15 mg·kg⁻¹; n = 6) (a), intratracheal nebulization of CMS (15 mg·kg⁻¹; n = 5) (b), and subcutaneous administration of colistin (1.5 mg·kg⁻¹; n = 6) (c).

FIG. 3.

Mean CMS and colistin concentrations (±SD) in ELF 30, 120, and 240 min after intratracheal nebulization of CMS (15 mg·kg⁻¹; n = 3 to 5 per time group).