title: 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" (Papp) of natural prostaglandins (PGF2alpha, PGD2 and PGE2), ester prodrugs of PGF2alpha (1-isopropyl PGF2alpha, 11-pivaloyl PGF2alpha and 11,15-dipivaloyl PGF2alpha) and four analogs (16-m-chlorophenoxy tetranor PGF2alpha, 17-phenyl trinor PGF2alpha, 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 Papp values ranged from 1.65 x 10(-6) to 2.38 x 10(-6) cm/sec), while the PGF2alpha prodrugs showed higher corneal penetration than PGF2alpha. The 11-pivaloyl ester of PGF2alpha penetrated the cornea faster than both 1-isopropyl ester and the lipophilic 11,15-dipivaloyl ester. The PG analogs also showed poor corneal penetration (Papp values ranged from 0.696 x 10(-6) to 1.49 x 10(-6) cm/sec) except for AH 13205. All compounds tested showed good scleral penetration (Papp values ranged from 6.90 x 10(-6) to 17.1 x 10(-6) cm/sec) except PGF2alpha 11,15-dipivaloyl (Papp = 1.22 x 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 PGF2alpha. 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.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, California 92713-9534, USA.
authors.forename: C
authors.initials: C
authors.lastname: Madhu
authors.forename: P
authors.initials: P
authors.lastname: Rix
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.forename: D S
authors.initials: DS
authors.lastname: Chien
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
authors.forename: D D
authors.initials: DD
authors.lastname: Tang-Liu
mesh_terms: D003315:Cornea / Q000378:metabolism*; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010539:Permeability; D011355:Prodrugs / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011465:Prostaglandins, Synthetic / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism*
chemical_list: D011355:Prodrugs; D011453:Prostaglandins; D011465:Prostaglandins, Synthetic; D015237:Dinoprost; D015232:Dinoprostone; D015230:Prostaglandin D2