Pharmacokinetics and Intraocular Pressure Lowering Effect of Timolol Preparations in Rabbit Eyes

Abstract

Two timolol preparations, a gel and an eyedrop with a thickening agent, and one commercial eyedrop without a thickening agent, were studied in rabbits. After topical administration of these three preparations in rabbits, aqueous humor was withdrawn and the proteins removed from the samples by precipitation with acetonitrile. Timolol concentrations were determined directly by an HPLC method. The HPLC mobile phase was composed of methanol and 5 mM d-camphorsulfonic acid (in 1% acetic acid) with a ratio of 49:51 (v/v). A reversed phase C18 column was used to separate samples with a flow rate of 0.8 mL/min and a UV detector set at 284 nm. A two-compartment pharmacokinetic model was used to fit the aqueous humor level for determining the drainage (kd) and absorption rate constants (ka) in the precorneal area as well as the elimination rate constant (ke) of timolol in aqueous humor. For ka +kd, the eyedrop without a thickening agent had the highest value (0.160 min-1), followed by the eyedrop with a thickening agent (0.030 min-1), and the gel had the lowest value (0.009 min-1). It suggests that the gel has a longer retention time in eyes to improve ocular bioavailability and decrease side effects. The AUC0 approximately infinity for the aqueous humor profile with time coordinates were 4142, 2974, and 1604 micrograms min/mL, for the gel, the eyedrop with a thickening agent, and the eyedrop without a thickening agent, respectively. In another study, timolol preparations were also topically administered in alpha-chymotrypsin-induced glaucoma rabbits for determining the lowering effect on intraocular pressure (IOP). The durations of depressing IOP for the gel, the eyedrop with a thickening agent, and the eyedrop without a thickening agent were 24, 14 and 10 hrs, respectively. Thus, the gel preparation has a longer duration and a higher ocular bioavailability which might be further developed in the treatment of open-angle glaucoma.

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

“…particularly in patients with comorbid conditions (i.e.. coronary heart disease, asthma). The gel preparation of timolol, with a thickening agent, has a longer duration and a higher ocular bioavailability, 35,3 which corresponds with our results. Carteolol is metabolized by the cytochrome P450 enzyme CYP2D6, which has a drug-metabolizing activity that is polymorphologically distributed in the popula-tion with less than 1% of Japanese individuals lacking normal activity, as opposed to 8% of European Americarns anld 2% to 4% of African Americans classified as poor metabolizer phenotypes.37'38 The genetically determined or pharmacologically induced poor metabolizer by CYP2D6 modulators is possibly susceptible to the systemic adverse effects of topical timolol or carteolol.5223940 Ocular instillation of a carteololophthalmic solution is recommended instead of nasal instillation to avoid systemic adverse effects, even in elderly patients, because ocular instillation can be a more effective and safer route in controlling IOP than nasal instillation.…”

Effects of Timolol and of Timolol with Tamarind Seed Polysaccharide on Intraocular Pressure in Rabbits

“…As a b-blocker, timolol may reduce blood pressure (Chiang et al 1996). There are con¯icting reports on the effects of b-adrenergic blockers on arterial blood pressure after topical application to the eye (Tagawa et al 1995;Tamaki et al 1997).…”

“…The discovery of methods to prolong the residence time of b-adrenergic blockers on the cornea is therefore of interest. Solutions of b-blockers are often made viscous by the addition of high molecular weight agents, such as water-soluble polymers of synthetic, semi-synthetic or natural origin (Chiang et al 1996). We suggest the use of tamarind seed polysaccharide (TS-P) (Int.…”

Sustained Delivery of Timolol Maleate for Over 90 Days by Subconjunctival Injection

“…In this study, the observed decrease in IOP is, while statistically highly significant, modest, but similar to that reported by other using normotensive rabbits. [30][31][32] In this proof of principle study, we did not intend to determine the amount of microbeads required to achieve, for example, a reduction of IOP by 5 mmHg since the pharmacokinetics of timolol differ between humans and rabbits. Indeed, previous studies have demonstrated that timolol is less effective in rabbits than humans, [33][34][35][36][37] suggesting that the use of timolol spheres may have a more marked effect in humans, and particularly in eyes with elevated IOP.…”