Evidence of the in vivo esterification of budesonide in human airways

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In vitro studies with human bronchial epithelial cells have shown that budesonide undergoes rapid, extensive and reversible intracellular esterification, a finding that is believed to contribute to retention and prolonged duration of action. • A case report has suggested retention of budesonide in the lungs of patients undergoing surgical resection. • This study evaluated, for the first time, the esterification (and distribution) of inhaled budesonide and fluticasone propionate in vivo in human lung. WHAT THIS STUDY ADDS • This study has unequivocally shown that budesonide undergoes esterification in human lungs in vivo. • Budesonide was detectable in central and peripheral lung tissue for 10 h, and budesonide oleate up to 43 h after inhalation. • The sustained retention of budesonide esters in the lungs probably contributes to the prolonged duration of action and once‐daily efficacy of budesonide. 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‐μg 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.

Formoterol and salmeterol induce a similar degree of β2‐adrenoceptor tolerance in human small airways but via different mechanisms

“…We have also shown that it produces similar effects to fluticasone propionate on chemokine expression (Banerjee et al, 2008). Further, in clinical studies, the budesonide concentration in airway and lung tissue (measured in central and peripheral lung), following a 1000 mg inhalation, approximates to 10 nM tissue concentration (van den Brink et al, 2008).…”

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

“…Similar tissue concentrations in rat trachea, and a 10-fold lower level in lung tissue, were earlier obtained in vivo after inhalation of BUD and FP (MillerLarsson et al, 1998) and recently after inhalation of CIC (Watz et al, 2006). The ϳ10 Ϫ8 M concentration in lung tissue corresponds to the levels obtained in humans 1 to 4 h after inhalation of high clinical doses (1-2 mg) of GCs (Van den Bosch et al, 1993;Esmailpour et al, 1997;Thorsson et al, 1998;Maassen van den Brink et al, 2005;Watz et al, 2006).…”

“…After inhalation, more than 50% of total BUD retained in the rat and human bronchial, nasal, and lung tissue is esterified at the carbon-21-hydroxyl group, primarily as BUD oleate (Miller-Larsson et al, 1998;Thorsson et al, 1998;Jendbro et al, 2001;Petersen et al, 2001;Maassen van den Brink et al, 2005). BUD esters are not active; i.e., they do not bind to glucocorticoid receptor (Wieslander et al, 1998), but they are hydrolyzed slowly, gradually releasing active BUD (Miller-Larsson et al, 1998;Wieslander et al, 1998).…”

Development of Budesonide Microparticles Using Spray-Drying Technology for Pulmonary Administration: Design, Characterization, In Vitro Evaluation, and In Vivo Efficacy Study

“…A dose-response relationship has been demonstrated for BUD (30,31) and an increase in the dose and frequency of BUD administration has been shown to be beneficial in quickly reducing inflammation and bronchoconstriction in patients with unstable asthma (28). Thus, inhaled corticosteroids should preferentially combine a high fraction of the dose that reaches the airways with a low swallowed fraction (32,33). Respirable fraction of currently available dry powder inhalation (DPI) formulations is not more than 30% (34)(35)(36), which means that only 30% of the total dose reaches the site of action, thus increasing frequency and dose of drug administration.…”