Effect of Bimatoprost on Intraocular Pressure in Prostaglandin FP Receptor Knockout Mice

• Published in: Investigative ophthalmology & visual science Vol. 46; no. 12; pp. 4571 - 4577
• Main Authors: Crowston, Jonathan G, Lindsey, James D, Morris, Christy A, Wheeler, Larry, Medeiros, Felipe A, Weinreb, Robert N
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.12.2005; Association for Research in Vision and Ophtalmology
• Subjects: Amides; Animals; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Aqueous Humor - metabolism; Bimatoprost; Biological and medical sciences; Blood-Aqueous Barrier - physiology; Cloprostenol - analogs & derivatives; Eye and associated structures. Visual pathways and centers. Vision; Eye Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gas Chromatography-Mass Spectrometry; Intraocular Pressure - drug effects; Lipids - pharmacokinetics; Lipids - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ophthalmic Solutions - pharmacokinetics; Ophthalmic Solutions - pharmacology; Receptors, Prostaglandin - deficiency; Receptors, Prostaglandin - physiology; Tonometry, Ocular; Vertebrates: nervous system and sense organs; Vertebrata; Mammalia; Gene; Prostaglandin; Mouse; Animal; Rodentia; Ophthalmology; Intraocular pressure
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.05-0723

To determine the effect of bimatoprost on intraocular pressure in the prostaglandin FP receptor knockout mouse. The IOP response to a single 1.2-microg (4 microL) dose of bimatoprost was measured in the treated and untreated fellow eyes of homozygote (FP+/+, n = 9) and heterozygote (FP+/-, n = 10) FP-knockout mice, as well as in wild-type C57BL/6 mice (FP+/+, n = 20). Serial IOP measurements were also performed after topical bimatoprost in a separate generation of homozygous FP-knockout mice and wild-type littermate control animals (n = 4 per group). Aqueous humor protein concentrations were measured to establish the state of the blood-aqueous barrier. Tissue, aqueous humor and vitreous concentrations of bimatoprost, latanoprost, and their C-1 free acids were determined by liquid chromatography and tandem mass spectrometry. A significant reduction in IOP was observed in the bimatoprost-treated eye of wild-type mice at 2 hours, with a mean difference and 95% confidence interval (CI) of the difference in means of -1.33 mm Hg (-0.81 to -1.84). Bimatoprost did not lead to a significant reduction in IOP in either the heterozygous knockout -0.36 mm Hg (-0.82 to +0.09) or homozygous FP-knockout mice 0.25 mm Hg (-0.38 to +0.89). The lack of an IOP response in the FP-knockout mice was not a consequence of blood-aqueous barrier breakdown, as there was no significant difference in aqueous humor protein concentration between treated and fellow eyes. Tissue and aqueous humor concentrations of bimatoprost, latanoprost, and their C-1 free acids indicate that latanoprost, but not bimatoprost, is hydrolyzed in the mouse eye after topical administration. An intact FP receptor gene is critical to the IOP response to bimatoprost in the mouse eye.