Ocular drug interactions involving topically applied timolol in the pigmented rabbit

The objective of this study was to determine whether the ocular and systemic absorption of topically applied timolol in the pigmented rabbit was significantly affected by the coadministration with other eye medications, including pilocarpine, epinephrine, their prodrugs, phenylephrine, tetracaine, and proparacaine. Twenty-five microliters of 0.65% timolol maleate solutions, both in the presence and absence of a second drug, were instilled to the pigmented rabbit eye. Timolol concentrations in anterior segment tissues were monitored at 30 and 90 min, and the time course of timolol concentration in plasma was monitored over 120 min. All coadministered drugs except proparacaine reduced intraocular timolol concentrations by varying extents depending on the sampling time, while increasing the timolol concentrations in the conjunctiva and sclera. In addition, all coadministered drugs, except pilocarpine, tetracaine, and proparacaine, reduced the systemic absorption of timolol by an average of about 50%. A plausible explanation for the simultaneous reduction in ocular and systemic timolol absorption is changes in tear turnover rate, protein secretion, and binding of timolol to tear proteins, rather than changes in corneal and perhaps conjunctival and nasal permeability, elicited by the second drug. Vasoconstriction on the conjunctival and nasal mucosae is an additional factor possibly contributing to the reduction in systemic timolol absorption by epinephrine, its prodrug, phenylephrine, and perhaps the pilocarpine prodrug. The clinical implication of the above findings is that before instituting combination or multiple drug therapy the possibility of changes in ocular and systemic absorption of the first drug by the second drug must be considered.