Variable Effects of Benzalkonium Chloride on β-Blocker Ocular Pharmacokinetics and Intraocular Pressure Lowering Efficacy

Abstract

Purpose: : Benzalkonium chloride (BAC) is a preservative often used in ophthalmic solutions and is also thought to increase the corneal penetration of some drugs. We determined in rabbits if BAC affects the pharmacokinetics and intraocular pressure (IOP) lowering effect of β-adrenergic blockers (timolol, catreolol and nipradilol).

Methods: : A single dose (50 µL) of 0.5% timolol with BAC (0.003%) or BAC-free was instilled into white rabbit eyes. Aqueous humor samples were collected at 10 and 30 min, 1, 2, 4, 6 and 8 h following administration. Drug concentrations were determined by high performance liquid chromatography. The same procedure was used with 1.0% carteolol and 0.25% nipradilol. The time dependent timolol IOP lowering effects up to 7 h were compared by applying on one eye either about 50 µL of 0.5% timolol with BAC, BAC-free or instead saline. Also the IOP lowering effects were measured of 1.0% carteolol with BAC (0.005%) and BAC-free. These drug effects in rabbits were compared with that of 0.25% nipradilol with BAC (0.01%) and BAC-free in healthy volunteers.

Results: : Both the ratio of the area under the curves from 0 to 4 h (AUC_0-4h) and that of the mean maximum concentrations (C_max) of timolol with BAC/BAC-free were 1.1. The ratio of AUC_0-8h and that of C_max of carteolol with BAC/BAC-free were 1.0 and 1.3, respectively. Both the ratio of AUC_0-2h and that of C_max of nipradilol with BAC/BAC-free were 0.7. There was no difference between either timolol with BAC and BAC-free or carteolol with BAC and BAC-free, nipradilol with BAC and BAC-free. Concerning IOP, timolol with BAC and BAC-free had hypotensive effects that were significantly greater than that of saline (P<0.01). The 90% confidence intervals for the difference in means of AUC_0-7h between timolol with BAC and BAC-free were -5.4 to 8.6 mmHg*h (-3.1 to 4.9%), which fell within the equivalence range (with BAC group’s mean ± 20%). Also, carteolol had equivalent efficacy irrespective of the presence or absence of BAC. Similarly, in healthy human volunteers, the IOP lowering efficacy of nipradilol was unchanged by BAC.

Conclusions: : BAC did not consistently increase either the pharmacokinetics of some β-adrenergic blockers or their IOP hypotensive effects under these conditions.

Keywords: cornea: basic science • intraocular pressure • aqueous