Comparison of the extrapulmonary beta2-adrenoceptor responses and pharmacokinetics of salbutamol given by standard metered dose-inhaler and modified actuator device.
1. Ten healthy subjects were randomised to inhale salbutamol via a standard metered-dose inhaler (MDI), or via a modified metered-dose actuator device (MA). Previously published radiolabelled aerosol data had shown that the MA device produced a lower aerosol velocity, reduced oropharyngeal deposition, but with unchanged pulmonary deposition. 2. Dose-response curves (DRC) were constructed with the following cumulative doses of salbutamol: 200 microg, 600 microg (200 microg + 400 microg), 1400 microg (600microg + 800 microg) ad 2600 microg (1400 + 1200 microg). Dose increments were made every 30 min and measurements of extrapulmonary beta2-adrenoceptor responses were performed 20 min after each dose. In addition, plasma salbutamol concentrations were also measured immediately before and for up to 60 min after the last dose. 3. Baseline values were not significantly different between the two study days for any of the measured parameters. 4. Cmax (ng ml(-1)) for plasma salbutamol (as means and 95% CI for difference between MA and MDI) was: 2.0 (0.3-3.7), P = 0.03. Values for t(max) (min), median and range: MA 5 (5-10) vs MDI 5 (5-10); and AUC 0-60, (ng ml(-1) min, mean and 95% CI for difference between MA and MDI): 69 (-5-143), were not significantly different between the two devices. 5. There was a significant (P < 0.01) left shift in the DRC with the MA device compared with the MDI, for hypokalaemic, finger tremor, chronotropic and electrocardiographic (Twave, Q-Tc) responses to salbutamol. Values for the hypokalaemic response (mmol l(-1)) at 2600 microg were (as change from baseline, means and 95% CI for difference between MA and MDI): 0.23 (0.10-0.36). 6. Thus, the MA device produced greater systemic absorption of salbutamol, and associated extrapulmonary beta2-adrenoceptor responses compared with a standard MDI. These results, therefore, suggest that data from radiolabelled aerosol deposition studies may not predict the systemic absorption of inhaled beta2-adrenoceptor agonists.
Newnham
D M
DM
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland.
McDevitt
D G
DG
Lipworth
B J
BJ
D000042:Absorption; D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers
D000318:Adrenergic beta-Agonists; D000420:Albuterol