COMPARISON OF THE EXTRAPULMONARY BETA(2)-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 mug, 600 mug (200 mug + 400 mug), 1400 mug (600 mug + 800 mug) ad 2600 mug (1400 + 1200 mug). 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 C(max) (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 1-1) at 2600 mug 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.