title: Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro.
abstract: We determined whether bimatoprost, which has been reported to act via putative prostamide receptors, could be hydrolyzed to its free acid (17-phenyl-PGF(2 alpha)), a potent FP receptor agonist, by human ocular tissue in vitro. We developed a gas chromatography/mass spectrometric method to measure 17-phenyl-PGF(2 alpha) levels at sub-picomolar levels. We then analyzed the amount of 17-phenyl-PGF(2 alpha) present after incubation of 50 microl Lumigan (0.03% bimatoprost) with eye tissue using this assay. We found that cornea, sclera, iris, and ciliary body, all rapidly hydrolyzed bimatoprost to 17-phenyl-PGF(2 alpha) with linear kinetics at a rate of 6.3, 2.0, 2.8, and 1.5 pmol mg tissue(-1) hr(-1), respectively. For cornea, sclera, and ciliary body, this linear rate of hydrolysis continued over a period of at least three hours, while iris-induced hydrolysis did not continue beyond one hour. Our findings suggest that bimatoprost can act as prodrug for FP receptor activation and questions the concept of a "prostamide receptor" agonist.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: Won-Kyu
authors.initials: WK
authors.lastname: Ju
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Neufeld
authors.forename: Daniel
authors.initials: D
authors.lastname: Abran
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
mesh_terms: D000577:Amides; D000818:Animals; D000069580:Bimatoprost; D002924:Ciliary Body / Q000378:metabolism; D003008:Cloprostenol / Q000031:analogs & derivatives; D003315:Cornea / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D005123:Eye / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007498:Iris / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008055:Lipids; D011355:Prodrugs / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism; D013552:Swine; D013997:Time Factors
chemical_list: D000577:Amides; D008055:Lipids; D011355:Prodrugs; D003008:Cloprostenol; C027042:17-phenylprostaglandin F2alpha; D015237:Dinoprost; D000069580:Bimatoprost