The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three β-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 μL/min, 687 μL, and 73.87 min), timolol (19.30 μL/min, 937 μL, and 33.64 min), and betaxolol (32.20 μL/min, 1421 μL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).
Ocular Intracameral Pharmacokinetics for a Cocktail of Timolol, Betaxolol, and Atenolol in Rabbits / Fayyaz, A.; Ranta, V. -P.; Toropainen, E.; Vellonen, K. -S.; Ricci, G. D.; Reinisalo, M.; Heikkinen, E. M.; Gardner, I.; Urtti, A.; Jamei, M.; Del Amo, E. M.. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 17:2(2020), pp. 588-594. [10.1021/acs.molpharmaceut.9b01024]