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Basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol
1University of Southern California, School of Pharmacy, Department of Pharmaceutical Sciences and Drug Targeting Center, Los Angeles, USA.
Summary
Diurnal variations in precorneal solution clearance influence ocular and systemic timolol absorption in rabbits. These changes, particularly slowest drainage at noon, impact drug absorption rates throughout the day.
Area of Science:
- Ophthalmology
- Pharmacokinetics
- Chronopharmacology
Background:
- Topical ocular drug delivery is influenced by physiological factors.
- Diurnal variations in ocular physiology may affect drug absorption.
- Understanding these variations is crucial for optimizing ophthalmic drug dosing.
Purpose of the Study:
- To investigate the basis for time-dependent changes in ocular and systemic absorption of topically applied timolol.
- To correlate precorneal solution retention and tissue permeability with dosing time.
Main Methods:
- Gamma scintigraphy to assess precorneal solution retention.
- Reversed-phase High-Performance Liquid Chromatography (HPLC) for timolol concentration analysis in plasma and ocular tissues.
- Modified Ussing chamber to evaluate corneal and conjunctival permeability.
- Studies conducted in pigmented rabbits at various dosing times.
Main Results:
- Precorneal solution drainage was slowest at noon.
- Anesthesia-induced suppression of tear production increased ocular timolol absorption at 6 a.m.
- No significant diurnal influence on systemic timolol absorption via nasal or conjunctival routes was observed.
- Diurnal changes in corneal permeability may also contribute to ocular absorption variations.
Conclusions:
- Diurnal changes in precorneal solution clearance are the primary factor driving time-dependent ocular and systemic timolol absorption in rabbits.
- Corneal permeability variations also play a role in diurnal ocular absorption.