AB - 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-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.