The Ocular Penetration and Intraocular Pressure Lowering Effect of Topical Acetaminophen in the New Zealand White Rabbit

Abstract

Purpose:

Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [N-arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR).

Methods:

A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs.

Results:

The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18–5.00) at 2 h and 0.92 ppm (0.60–1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was −5.1 mmHg⋅h (95% CI: −10 to 0.41) for control,−7.5 mmHg⋅h (95% CI: −14 to −1.1) for half-hourly acetaminophen, and −4.4 mmHg⋅h (95% CI: −14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was −2.3 mmHg⋅h (95% CI: −5.9 to 1.3) for control,−2.0 mmHg⋅h (95% CI: −5.6 to 1.7) for AM404, −1.7 mmHg⋅h (95% CI: −4.5 to 1.2) for acetaminophen, and −3.2 mmHg⋅h (95% CI: −5.4 to −0.96) for acetaminophen/AM404 combined.

Conclusions:

Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.