Eyedrops containing SA9000 prodrugs result in sustained reductions in intraocular pressure in rabbits.
OBJECTIVE
Poor topical bioavailability and ocular irritation have impeded the development of the diuretic, ethacrynic acid (ECA) as a clinically useful ocular hypotensive for the treatment of glaucoma. Thus, the development of analogs and prodrugs of analogs with improved ocular penetration, potency, and tolerability is required. The aim of this work is to evaluate the corneal penetration and ocular distribution of SA9000, an ECA analog. Novel SA9000 prodrugs intended to further improve ocular pharmacodynamic effect were also evaluated.


RESULTS
SA9000 penetrated porcine corneas more effectively than ECA in corneal diffusion studies. In vivo studies in Dutch-belted (DB) rabbits indicated that topical application of a single dose (0.3%) of SA9000 could significantly reduce intraocular pressure (IOP) (approximately 25% vs. fellow untreated eye) but caused significant conjunctival hyperemia. Since this hyperemia was likely the result of its inherent thiol reactivity, SA9000 was formulated with equimolar cysteine, an exogenous thiol donor. The administration of increasing SA9000-cysteine adduct concentrations (0.3%, 0.6%, 0.9%) demonstrated that they cause less ocular irritation than unadducted SA9000 but could still significantly reduce IOP (0.3%: 8.7 +/- 2%; 0.6%: 14.4 +/- 5%; 0.9%: 23.3 +/- 4.4%) versus untreated contralateral control eyes.


CONCLUSIONS
These data suggest that novel thiol donor adduction can improve the ocular bioavailability and tolerability of SA9000. SA9000-cysteine prodrugs may represent a new option for the topical treatment of glaucoma.
Arnold
John J
JJ
Department of Ophthalmology, Duke University School of Medicine, Duke University, Durham, NC 27710, USA.
Choksi
Yash
Y
Chen
Xin
X
Shimazaki
Atsushi
A
Hatten
John
J
Toone
Eric J
EJ
Epstein
David L
DL
Challa
Pratap
P
D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003228:Conjunctiva / Q000098:blood supply / Q000187:drug effects; D003229:Conjunctival Diseases / Q000139:chemically induced; D003315:Cornea / Q000378:metabolism; D003545:Cysteine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004976:Ethacrynic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006940:Hyperemia / Q000139:chemically induced; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009883:Ophthalmic Solutions; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits
D002934:Cinnamates; D004338:Drug Combinations; D009883:Ophthalmic Solutions; D011355:Prodrugs; C496163:SA9000; D003545:Cysteine; D004976:Ethacrynic Acid