Abstract
The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs.
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REFERENCES
W. L. Nelson, F. L. Fraunfelder, J. M. Sills, J. B. Arrowsmith, and J. N. Kuritsky. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978–1985. Am. J. Ophthalmol. 102:606–611 (1986).
S. C. Chang, H. Bundgaard, A. Buur, and V. H. L. Lee. Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load. Invest. Ophthalmol. Vis. Sci. 28:487–491 (1987).
S. C. Chang, H. Bundgaard, A. Buur, and V. H. L. Lee. Low dose O-butyryl timolol improves the therapeutic index of timolol in the pigmented rabbit. Invest. Ophthalmol. Vis. Sci. 29:626–629 (1988).
H. Bundgaard, A. Buur, S. C. Chang, and V. H. L. Lee. Timolol prodrugs: Synthesis, stability and lipophilicity of various alkyl, cycloalkyl, and aromatic esters of timolol. Int. J. Pharm. 46:77–88 (1988).
S. C. Chang, D. S. Chien, H. Bundgaard, and V. H. L. Lee. Relative effectiveness of prodrug and viscous solution approaches in maximizing the the ratio of ocular to systemic absorption of topically applied timolol. Exp. Eye Res. 46:59–69 (1988).
S. C. Chang and V. H. L. Lee. Nasal and conjunctival contributions to the systemic absorption of topical timolol in the pigmented rabbit: Implications in the design of strategies to maximize the ratio of ocular to systemic absorption. J. Ocular Pharmacol. 3:159–169 (1987).
M. G. Doane, A. D. Jensen, and C. H. Dohlman. Penetration routes of topically applied eye medications. Am. J. Ophthalmol. 85:383–386 (1978).
H. Bundgaard, A. Buur, and V. H. L. Lee. Timolol prodrugs: Preparation and hydrolysis kinetics of N-benzoyl carbamate esters of timolol and related compounds. Acta Pharm. Suec. 25:293–306 (1988).
V. H. L. Lee, D. S. Chien, and H. Sasaki. Ocular ketone reductase distribution and its role in the metabolism of ocularly applied levobunolol in the pigmented rabbit. J. Pharmacol. Exp. Ther. 246:871–878 (1988).
M. Bradford. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248–254 (1976).
H. F. Edelhauser, J. R. Hoffert, and P. O. Fromm. In vitro ion and water movement in corneas of rainbow trout. Invest. Ophthalmol. 4:290–296 (1965).
D. S. Chien, H. Bundgaard, and V. H. L. Lee. Influence of corneal epithelial integrity on the penetration of timolol prodrugs. J. Ocular Pharmacol. 4:137–145 (1988).
R. D. Schoenwald and R. L. Ward. Relationship between steroid permeability across excised rabbit cornea and octanol-water partition coefficients. J. Pharm. Sci. 67:786–788 (1978).
G. L. Mosher and T. J. Mikkelson. Permeability of the n-alkyl p-aminobenzoate esters across the isolated corneal membrane of the rabbit. Int. J. Pharm. 2:239–243 (1979).
K. Kishida and T. Otori. A quantitative study on the relationship between transcorneal permeability of drugs and their hydrophobicity. Jpn. J. Ophthalmol. 24:251–259 (1980).
R. D. Schoenwald and H. S. Huang. Corneal penetration behavior of β-blocking agents. I. Physicochemical factors. J. Pharm. Sci. 72:1266–1272 (1983).
G. M. Grass and J. R. Robinson. Relationship of chemical structure to corneal penetration and influence of low-viscosity solution on ocular bioavailability. J. Pharm. Sci. 73:1021–1027 (1984).
R. O. Potts, S. C. McNeill, C. R. Desbonnet, and E. Wakshull. Transdermal drug transport and metabolism. II. The role of competing kinetic events. Pharm. Res. 6:119–124 (1989).
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Chien, DS., Sasaki, H., Bundgaard, H. et al. Role of Enzymatic Lability in the Corneal and Conjunctival Penetration of Timolol Ester Prodrugs in the Pigmented Rabbit. Pharm Res 8, 728–733 (1991). https://doi.org/10.1023/A:1015845916293
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DOI: https://doi.org/10.1023/A:1015845916293