Penetration of Natural Prostaglandins and Their Ester Prodrugs and Analogs Across Human Ocular Tissues in Vitro

ABSTRACT

The objective of this study was to assess the corneal and scleral permeabilities of natural prostaglandins as well as their prodrugs and analogs through human cornea and sclera in vitro. The "apparent permeability coefficients" (P_app) of natural prostaglandins (PGF_2α, PGD₂ and PGE₂), ester prodrugs of PGF_2α (1-isopropyl PGF_2α, 11-pivaloyl PGF_2α and 11,15-dipivaloyl PGF_2α) and four analogs (16-m-chlorophenoxy tetranor PGF_2α, 17-phenyl trinor PGF_2α, 17-phenyl trinor PGE₂ and AH 13205) were measured using modified Ussing perfusion chambers and quantitative high performance liquid chromatography. Our results indicate that the corneal penetration of natural prostaglandins (PGs) is poor (the P_app values ranged from 1.65 × 10⁻⁶ to 2.38 × 10⁻⁶cm/sec), while the PGF_2α prodrugs showed higher corneal penetration than PGF_2α. The 11-pivaloyl ester of PGF_2α penetrated the cornea faster than both 1-isopropyl ester and the lipophilic 11,15-dipivaloyl ester. The PG analogs also showed poor corneal penetration (P_app values ranged from 0.696 × 10⁻⁶ to 1.49 × 10⁻⁶ cm/sec) except for AH 13205. All compounds tested showed good scleral penetration (P_app values ranged from 6.90 × 10⁻⁶ to 17.1 × 10⁻⁶ cm/sec) except PGF_2α 11,15-dipivaloyl (P_app = 1.22 × 10⁻⁶ cm/sec). The penetration profiles correlated well with tissue uptake ratios (ratio of final tissue concentration to initial dose) for all compounds except 11,15-dipivalate PGF_2α. All ester prodrugs (but not the PGs and analogs) underwent corneal first-pass metabolism. The study results demonstrate that transcleral absorption may play a significant role in the ocular absorption of these compounds.