title: The hydrolysis of the prostaglandin analog prodrug bimatoprost to 17-phenyl-trinor PGF2alpha by human and rabbit ocular tissue.
abstract: Bimatoprost (Lumigan), the ethyl amide derivative of the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha), has been reported to be a member of a pharmacologically unique class of ocular hypotensive agents. To confirm that bimatoprost, which is intrinsically active as an FP prostaglandin agonist, is also a prostaglandin analog prodrug, the hydrolysis of bimatoprost by ocular tissues was studied by incubating solutions containing bimatoprost with either human or rabbit ocular tissue. The ethyl amide group of bimatoprost was hydrolyzed by rabbit and human cornea, iris/ciliary body and Thasclera to produce the expected carboxylic acid product, 17-phenyl-trinor PGF(2alpha). The rate of hydrolysis by human and rabbit cornea and iris/ciliary body is similar, whereas the rate of hydrolysis by the sclera is slower in humans than in rabbits. These studies show that human and rabbit ocular tissue (cornea, iris/ciliary body and sclera) can convert bimatoprost to the potent prostaglandin FP agonist 17-phenyl-trinor PGF(2alpha). Separate in vitro studies clearly show that both bimatoprost and 17-phenyl-trinor PGF(2alpha) have affinity for and are agonists at the human FP receptor. Taken together, the data strongly suggests that the ocular hypotensive effect of bimatoprost can be attributed to its activity as a prostaglandin receptor agonist either directly or through its role as a prostaglandin agonist prodrug.
authors.affiliation: Alcon Research Ltd., Fort Worth, Texas 76134, USA. mark.hellberg@alconlabs.com
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellberg
authors.forename: Tai-Lee
authors.initials: TL
authors.lastname: Ke
authors.forename: Karen
authors.initials: K
authors.lastname: Haggard
authors.forename: Peter G
authors.initials: PG
authors.lastname: Klimko
authors.forename: Tom R
authors.initials: TR
authors.lastname: Dean
authors.forename: Gustav
authors.initials: G
authors.lastname: Graff
mesh_terms: D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D002851:Chromatography, High Pressure Liquid; D002924:Ciliary Body / Q000378:metabolism*; D003008:Cloprostenol / Q000031:analogs & derivatives; D003315:Cornea / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007498:Iris / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids; D011817:Rabbits; D012590:Sclera / Q000378:metabolism*
chemical_list: D000577:Amides; D008055:Lipids; C013646:17-phenyl-18,19,20-trinorprostaglandin F2 alpha; D003008:Cloprostenol; D015237:Dinoprost; D000069580:Bimatoprost