Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.