Clinical pharmacokinetics of inhaled budesonide

The corticosteroid budesonide is a 1 : 1 racemic mixture of 2 epimers, (22R ) and (22S)-, and is available in 3 different inhaled formulations for the management of asthma: a pressurised metered dose inhaler (pMDI), a dry powd er inhaler (DPI) and a solution for nebulised therapy. Inhaled corticostero ids such as budesonide reach the systemic circulation either by direct abso rption through the lungs (a route that is much more important than previous ly recognised) or via gastrointestinal absorption of drug that is inadverte ntly swallowed. Although the pharmacokinetics of budesonide have been exten sively investigated following oral and intravenous administration, relative ly few studies have defined the systemic disposition of budesonide after in halation. Drug deposition in the lungs depends on the inhaler device: 15 % of the met ered dose of budesonide reached the lung with a pMDI compared with 32% with a breath-actuated DPI. In patients with asthma (n = 38) receiving differen t doses of budesonide by DPI (Turbuhaler (R)), the pharmacokinetic paramete rs peak plasma concentration (C-max) and area under the concentration-time curve (AUC) were dose-dependent after both single dose and repeat dose (3 w eeks) administration;time to C-max (t(max)) was Short (0.28 to 0.40 hours) and the elimination half-life approximately 3 hours. Both AUC and C-max wer e linearly related to budesonide dose. In a small group of healthy male vol unteers (n = 9), the pharmacokinetics of budesonide 1600 mug twice daily vi a pMDI were assessed on the fifth day of administration. Mean model-indepen dent parameters for (22R)-budesonide were as follows: C-max 1.8 mug/L, t(ma x) 0.46 hours, elimination half-life 2.3 hours and oral clearance 163 L/h, and there were no enantiomer-specific differences in drug disposition. Budesonide undergoes fatty acid conjugation within the lung, but very limit ed pharmacokinetic data are available to define the pulmonary absorption ch aracteristics. There is evidence from a population analysis that the pulmon ary absorption of budesonide is prolonged and shows wide interindividual va riation. Further pharmacokinetic studies are required to define the time-co urse of budesonide absorption through the lung in specific patient groups, and to investigate the effect of new inhaler devices (especially chlorofluo rocarbon-free pMDIs) on the pharmacokinetic profile and systemic drug expos ure.