Systemic absorption pathways of topically applied beta adrenergic antagonists in the pigmented rabbit

The objective of this study was to determine the influence of drug lipophilicity on extent of systemic absorption and relative contributions of the nasal and conjunctival mucosae to systemic absorption following topical solution instillation in the pigmented rabbit. Relatively hydrophilic atenolol, moderately lipophilic timolol and levobunolol, and lipophilic betaxolol were chosen as model drugs. Twenty-five microliters of a 15 mM drug solution in isotonic pH 7.4 buffer was instilled in each eye, with or without nasolacrimal occlusion, and plasma drug concentration was monitored using reversed phase HPLC. An equivalent amount of all four beta adrenergic antagonists was instilled directly into the nasolacrimal duct to assess the nasal contribution to systemic drug absorption following topical solution instillation. The systemic bioavailability ranged from 61% for atenolol to 100% for timolol. At least 50% of the systemically absorbed drug reached the bloodstream from the nasal mucosa; the nasal contribution was 83% for atenolol and 55-74% for the other three drugs. Occluding the nasolacrimal duct for 5 min reduced the extent of systemic absorption of timolol and levobunolol but did not do so for atenolol and betaxolol. Additional prolongation of solution retention in the conjunctival sac brought about further reduction for only atenolol (480-min prolongation) and timolol (120-min prolongation). Taken together, the above findings suggest that the systemic bioavailability of topically applied ophthalmic drugs would be modest for drugs at the extremes of lipophilicity and that the contribution of the nasal pathway to systemically absorbed drug diminishes with increasing drug lipophilicity.