Evidence of the in vivo esterification of budesonide in human airways

Abstract

Aims: Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans.

Methods: This open-label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000-mug doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry.

Results: Lung tissue samples were obtained from 22 patients at surgery, 1-43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen.

Conclusion: Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once-daily administration.

Figure 1

Concentrations of (a) budesonide, (b) budesonide oleate and (c) fluticasone propionate in central and peripheral lung tissue, in brush samples and intercostal muscle from the time of inhalation to 22 h afterwards. A sample obtained at 29 h had no detectable corticosteroid levels, a further sample at 43 h contained detectable budesonide-oleate in peripheral lung tissue. Tissue concentrations are shown on logarithmic scales. Dotted line represents limit of quantification. Bronchial, (○); Central, (□); Peripheral, (▵); Muscle, (+)

Figure 2

Individual plasma concentration–time curves for (a) budesonide and (b) fluticasone propionate. Dotted line represents limit of quantification