The long-term goal of this research is to broaden the applications of prodrugs in ocular drug therapy. The immediate goal is to understand three factors that could influence the therapeutic effectiveness of prodrugs through their direct or indirect influence on ocular esterase activity and prodrug conversion: route of drug entry to the ciliary body (non-corneal vs. corneal), vehicle composition, and the co-administration of another drug for control of glaucoma or other ocular conditions. The focus will be on 0-1'-methylcyclopropanoyl timolol, which in terms of chemical stability and ratio of ocular to systemic drug absorption is the best candidate of 25 prodrugs tested. There are three specific aims in this research: (1) To determine whether the non-corneal route of ocular penetration is favored by certain timolol prodrugs and whether this preference constitutes an additional factor in their enhanced and prolonged ocular Beta adrenergic blockade, and to delineate the prodrug and vehicle characteristics promoting non- corneal penetration, (2) To determine whether the therapeutic index of 0-1'-methylcyclopropanoyl timolol can be improved by drug vehicles with the proper precorneal retention and drug release characteristics, and (3) To elucidate the mechanisms underlying the pharmacokinetic and pharmacodynamic changes of 0-1'- methylcyclopropanoyl timolol upon co-administration with other glaucoma drugs such as pilocarpine, epinephrine, and their prodrugs, or with other ocular drugs such as phenylephrine and proparacaine. The principal methodology includes (1) the use of perfusion chambers to evaluate drug permeation, (2) the sampling of plasma and selected anterior and posterior segment tissues at various times following prodrug administration for determination of systemic and ocular drug bioavailability using HPLC with radiochemical and spectrophotometric detection, and (3) measurement of the time course of intraocular pressure changes in the water- loaded pigmented rabbit using the pneumatonometer. The importance of this research is that it shows how the effectiveness of prodrugs for the control of glaucoma (and other eye diseases) can be maximized by optimizing the vehicle characteristics with respect to precorneal drug retention and enhancement of non-corneal drug penetration. Moreover, the information on drug interactions should enable one to judiciously evaluate the therapeutic benefit of drug combinations to rationally plan a dosing regimen for multiple drug therapy, and to rationally establish the optimal concentration of each drug in a combination.
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