Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog.

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm(-2) hr(-1), dependent on the formulation. The transdermal flux of timolol in the dog was greater than 10 µg cm(-2) hr(-1). This estimate was based on the degree of antagonism of isoproterenol challenge following transdermal administration of timolol relative to that obtained following intravenous administration of timolol. Irritation was observed in the rat after occluded dermal application of timolol free base but was not observed when the concentration of the drug in the formulation was decreased.