Low dose O-butyryl timolol improves the therapeutic index of timolol in the pigmented rabbit.

The degree of enhancement in the ocular absorption of timolol afforded by its O-butyryl prodrug and the possibility of reducing its systemic absorption through a proportional reduction in its instilled dose were investigated in the pigmented rabbit. A reversed phase HPLC procedure was used to assay for timolol and O-butyryl timolol in the aqueous humor and plasma over 120 min post-instillation of 25 microliter of drug solutions. We found that the ocular absorption of the O-butyryl prodrug of timolol from a 15 mM solution was 5.5 times greater than that of the parent drug while the systemic absorption was comparable. When a lower concentration of the prodrug (3.75 mM) was used the therapeutic index as assessed by the ratio of aqueous humor to plasma concentrations seemed to improve fifteenfold. Therefore, it is possible to significantly reduce the systemic absorption of timolol without reducing its ocular absorption by using a low dose of its O-butyryl prodrug.