Aerosol therapy with colistin methanesulfonate: a biopharmaceutical issue illustrated in rats
Sandrine Marchand1, Patrice Gobin, Julien Brillault
1INSERM ERI-23, 40 Avenue du Recteur Pineau, 86000 Poitiers, France.
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.
Insights
Nebulized colistin methanesulfonate (CMS) in rats leads to higher systemic colistin levels compared to intravenous administration. This suggests intratracheal nebulization enhances colistin bioavailability for potential antimicrobial activity.
Area of Science:
- Pharmacokinetics and Biopharmaceutics
- Drug Delivery and Administration
- Infectious Diseases and Microbiology
Background:
- Colistin methanesulfonate (CMS) is a prodrug of colistin, an antibiotic used against multidrug-resistant Gram-negative bacteria.
- Understanding the biopharmaceutical behavior of CMS, particularly its conversion to active colistin after nebulization, is crucial for optimizing its therapeutic use.
- Previous studies have established baseline pharmacokinetic parameters for colistin and its prodrugs.
Purpose of the Study:
- To evaluate the biopharmaceutical behavior of colistin methanesulfonate (CMS) following intratracheal nebulization in rats.
- To investigate the presystemic formation of colistin from CMS after nebulization.
- To compare the systemic pharmacokinetics and lung concentrations of colistin after CMS nebulization versus intravenous administration.
Main Methods:
- Colistin methanesulfonate (CMS) was administered intravenously or via intratracheal nebulization to rats.
- Systemic pharmacokinetic studies were conducted using noncompartmental analysis.
- Colistin and CMS concentrations in epithelial lining fluid (ELF) and plasma were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
Main Results:
- The systemic conversion of intravenous CMS to colistin was approximately 12.5%.
- After nebulization, about two-thirds of the CMS dose was directly absorbed systemically, while one-third was converted to colistin before absorption.
- Colistin's area under the curve (AUC) was approximately 4-fold greater after nebulization (607 ± 240 μg·min·mL⁻¹) compared to intravenous administration (160 ± 20 μg·min·mL⁻¹).
- High CMS concentrations were observed in ELF shortly after nebulization, with significant colistin concentrations also detected, potentially sufficient for antimicrobial activity.
Conclusions:
- Intratracheal nebulization of CMS significantly enhances systemic colistin availability compared to intravenous administration in rats.
- A substantial portion of nebulized CMS is converted to active colistin, contributing to increased systemic exposure.
- Colistin concentrations achieved in the lung epithelial lining fluid after nebulization may be therapeutically relevant for treating respiratory tract infections.
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