BASIS FOR DOSING TIME-DEPENDENT CHANGES IN THE OCULAR AND SYSTEMIC ABSORPTION OF TOPICALLY APPLIED TIMOLOL

The objective of the present study was to determine the basis for dosi ng time-dependent changes in the ocular and systemic absorption of top ically applied timolol in pigmented rabbits. The gamma scintigraphic t echnique was used to monitor the changes in precorneal solution retent ion following instillation. Changes in timolol concentration in the pl asma over 120 min and in various anterior segment eye tissues at 30 mi n following the topical instillation of 25 mu l of 0.65% timolol malea te solutions at various dosing times were monitored using reversed pha se HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated t hat precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorpt ion at 6 a.m. but not at other dosing times, in spite of the lowest co rneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conj unctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal chan ges in ocular as well as systemic timolol absorption in rabbits. In ad dition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.