Marked differential effects of prostanoid metabolites on rabbit intraocular pressure.
A comparison of the effects of the major metabolites of prostaglandins E2, F2 alpha, and D2 (PGE2, PGF2 alpha and PGD2) on rabbit intraocular pressure (IOP) revealed differences in potency relative to each other and the parent prostanoid. 15-Keto PGF2 alpha produced significant, dose-dependent decreases in IOP at 0.1 and 1% doses; responses of a similar magnitude were achieved with 0.01 and 0.1% PGF2 alpha indicating a 10-fold difference in potency between PGF2 alpha and its 15-keto metabolite. 13,14-Dihydro PGF2 alpha appeared slightly less active than 15-keto PGF2 alpha, whereas 13,14-dihydro-15-keto PGF2 alpha was almost 100-fold less potent than PGF2 alpha. PGE2 was approximately 100-fold more potent as an ocular hypotensive than its 15-keto and 13,14-dihydro-15-keto metabolites. 19(R)-OH PGF2 alpha did not alter IOP, whereas 19(R)-OH PGE2 was essentially equipotent to PGE2 as an ocular hypertensive without producing the typical subsequent decrease in IOP. The decrease in IOP evoked by active PGE2 and PGF2 alpha metabolites was of shorter duration than responses produced by the respective parent prostanoid. Although PGD2 was equipotent with PGE2 and PGF2 alpha, the 11-ketoreductase-derived metabolite (9 alpha, 11 beta-PGF2) exhibited little effect on IOP, and 13,14-dihydro-15-keto PGD2 was inactive. The thromboxane A2 (TxA2)-mimetic U-46619 and TxB2 did not significantly alter IOP.(ABSTRACT TRUNCATED AT 250 WORDS)
Woodward
D F
DF
Allergan, Inc., Discovery Research Department, Irvine, Calif.
Williams
L S
LS
Chen
J
J
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000287:Administration, Topical; D000818:Animals; D003315:Cornea / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D015230:Prostaglandin D2 / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013928:Thromboxane A2 / Q000494:pharmacology; D013929:Thromboxane B2 / Q000494:pharmacology; D013997:Time Factors
D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D015232:Dinoprostone; D015230:Prostaglandin D2