Analysis of Fenoterol and Ipratropium Transfer from Human Lung Tissue into Human Plasma Using a Dynamic Dialysis Model

Beatrice Trammer

doi:10.9734/bjpr/2014/9993

Abstract

Aims: The aim of the current study was to establish a simple and yet as much as possible physiologic approach for a simulation of the pulmonary absorption process to compare different inhaled drugs or drug formulations. Methodology: We designed a dialysis setting that allowed monitoring the drug release from human lung tissue into a continuous-flow plasma compartment. For proof-of-concept experiments we chose the glucocorticoid fluticasone propionate (FP) as model compound. For subsequent experiments we selected a commercially available metered dose inhaler delivering a fixed combination of the short-acting s2-agonist fenoterol and the muscarinic antagonist ipratropium bromide. Results: With the novel dynamic dialysis model we observed high drug transport rates from the lung tissue into plasma including an elimination phase. The concentration profile in the plasma compartment of our model system was similar to the plasma concentration courses after inhalation of FP. Compared to FP significantly higher drug fractions of fenoterol and ipratropium bromide were released into plasma and the transfer of ipratropium was more pronounced compared to fenoterol. Again, concentration profiles in plasma were alike to those described in clinical studies. Conclusion: We suggest that this model is appropriate for rapid assessment of comparative diffusion behaviour of drugs or drug formulations from lung tissue into plasma.

Highlights

The efficacy and safety of inhaled drugs are dependent on the compounds’ pharmacokinetics which in turn is governed by the physicochemical properties of the drug and by its formulation
Fluticasone propionate (FP) was a generous gift from GlaxoSmithKline (Greenford, England), amcinonide, fenoterol hydrobromide (Feno-HBr), ipratropium bromide (Ipra-Br), salbutamol sulfate (Salb-S) and the dye Fast Green FCF were purchased at Sigma Aldrich (Taufkirchen, Germany)
In the static dialysis experiments the concentration of fluticasone propionate (FP) increased continuously from 45±13ng/mL after 3min to 739±11ng/mL after 240min Fig. 2

Summary

Introduction

The efficacy and safety of inhaled drugs are dependent on the compounds’ pharmacokinetics which in turn is governed by the physicochemical properties of the drug and by its formulation. Up to 60-90% of an inhaled drug are deposited in the oropharyngeal region and are subsequently swallowed [2]. Analysis of pulmonary deposition and regional particle distribution can be achieved by gamma scintigraphy after inhalation of radiotracer-labeled drugs. This complex method is typically not applicable for routine measurements. It has been proposed that pharmacokinetic data well reflect pulmonary drug deposition and that pulmonary drug absorption can be elucidated using pharmacokinetic methods [2]. Pharmacokinetic data have been discussed as key indicator of bioequivalence for inhaled drug products [3]

Methods

Results

Conclusion