Ocular penetration and bioconversion of prostaglandin F-2 alpha prodrugs in rabbit cornea and conjunctiva

The objective of this study was to identify prostaglandin F-2 alpha (PGF(2 alpha)) prodrugs that have an optimal ocular absorption profile and therefore could be potentially useful for the treatment of glaucoma. Rabbit cornea, conjunctiva, and iris/ciliary body were mounted in a flow-through chamber to evaluate the permeability and bioconversion of PGF(2 alpha) and its prodrugs. The prodrugs tested were PGF(2 alpha) l-isopropyl, 1,ll-lactone, 15-acetyl, 15-pivaloyl, 15-valeryl, and 11,15-dipivaloyl esters. After 4 h in the donor or acceptor compartments, the products and formation of PGF(2 alpha) were analyzed by HPLC. Effects on intraocular pressure and ocular surface hyperemia were also determined. All prodrugs penetrated the rabbit cornea faster than PGF(2 alpha) by 4- to 83-fold. All prodrugs penetrated conjunctiva faster than PGF(2 alpha), except the 15-acetyl ester prodrug, which was equally permeable. No direct correlation between drug lipophilicity and permeability across the cornea or conjunctiva was apparent. The most metabolically stable prodrug was the I,ll-lactone, followed by the 11,15-dipivaloyl, 15-pivaloyl, 15-acetyl, l-isopropyl, and the 15-valeryl esters, the latter of which was extensively converted to PGF(2 alpha). A separation index for various prodrugs was calculated from the ratio of the bioavailable PGF(2 alpha) for ocular hypotension to the bioavailable PGF(2 alpha) for hyperemia. The highest separation index was observed for the 1,ll-lactone prodrug (2.33), followed by the 11,15-dipivaloyl ester prodrug (1.80). Thus the I,ll-lactone and 1 I,15-dipivaloyl ester prodrugs appeared to be superior to the others in providing bioavailable PGF(2 alpha) for ocular hypotension, while minimizing hyperemia. The favorable separation index for these compounds appeared to be due to their metabolic stability at the corneal surface and conjunctiva combined with sufficient bioavailability for ocular hypotension.