Abstract
The O-acetyl, propionyl, butyryl and pivaloyl esters of timolol were synthesized and evaluated as prodrugs for potential in diminishing the systemic absorption and therefore side effects of topically applied timolol through increased corneal permeation. The esters showed a 14–525-fold increase in lipophilicity relative to timolol as determined by partition experiments in octanol-pH 7.4 buffer. They all were hydrolyzed to yield timolol in quantitative amounts in buffer solutions, human plasma and homogenates of the conjunctiva, corneal epithelium and iris-ciliary body of the pigmented rabbit. At pH 7.4 and 37°C, the half-lives of chemical hydrolysis were 28, 40, 50 and 215 min for the O-acetyl, propionyl, butyryl and pivaloyl esters, respectively. Human plasma did not catalyze the hydrolysis but showed instead a rate-decelerating effect. Such an effect was also observed with tromethamine (Tris) at neutral pH. However, the esters were 1.5-2 times more susceptible to hydrolysis in ocular tissue homogenates than in buffer. Hydrolysis was most rapid for the butyryl ester, followed, in turn, by the propionyl, acetyl and pivaloyl esters. For a given prodrug, hydrolysis proceeded most readily in the iris-ciliary body, followed by conjunctiva and corneal epithelium.
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