Basis for Dosing Time-Dependent Changes in the Ocular and Systemic Absorption of Topically Applied Timolol

Abstract

The objective of the present study was to determine the basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol in pigmented rabbits. The gamma scintigraphic technique was used to monitor the changes in precorneal solution retention following instillation. Changes in timolol concentration in the plasma over 120 min and in various anterior segment eye tissues at 30 min following the topical instillation of 25 microliters of 0.65% timolol maleate solutions at various dosing times were monitored using reversed phase HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated that precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorption at 6 a.m. but not at other dosing times, in spite of the lowest corneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conjunctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal changes in ocular as well as systemic timolol absorption in rabbits. In addition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.

Pharmacokinetic and Pharmacodynamic Differences between Ocular and Nasal Instillation of Carteolol on Intraocular Pressure and Heart Rate in Japanese Men with High CYP2D6 Activity

“…The absorption phase after nasal dosing is reported faster than that after ocular dosing in rabbits. 24 The blood samples in this study were collected more frequently during the first hour after drug administration than in other studies.…”

Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics

“…Changes in the ocular absorption of topically applied timolol were reported as dosing‐time dependent (Lee et al, 1996; Ohdo, Grass, & Lee, 1991). Corneal and conjunctival permeabilities were significantly lower at light onset (ZT 0; Lee et al, 1996), but the lowest values of C max and AUC were observed later at ZT 6 (Table 2).…”

“…Changes in the ocular absorption of topically applied timolol were reported as dosing‐time dependent (Lee et al, 1996; Ohdo, Grass, & Lee, 1991). Corneal and conjunctival permeabilities were significantly lower at light onset (ZT 0; Lee et al, 1996), but the lowest values of C max and AUC were observed later at ZT 6 (Table 2). Even though the mechanisms behind variations in ocular PK are not yet completely understood, a circadian disruption of intercellular junctional proteins (occludin, claudin‐4) in the corneal epithelium of Xenopus laevis was observed during the night (Wiechmann, Ceresa, & Howard, 2014).…”