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NA Sharif, TL Ke, K Haggard, CR Kelly, GW Williams, G Graff, MR Hellberg, TR Dean; Bimatoprost Hydrolysis to 17-Phenyl PGF2alpha by Human and Rabbit Ocular Tissues and Agonist Activity of Bimatoprost and 17-Phenyl PGF2alpha . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4080.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Bimatoprost is the ethyl amide prodrug of the potent prostaglandin FP agonist, 17-Phenyl PGF2α. The hydrolysis of bimatoprost by ocular tissues was studied by incubating solutions containing bimatoprost with either human or rabbit ocular tissues. The FP prostaglandin receptor affinity and agonist activity of both the prodrug bimatoprost and 17-Phenyl PGF2α were also determined. Methods: A 0.01% solution of bimatoprost in glutathione-supplemented bicarbonate Ringer buffer was incubated with freshly dissected human or rabbit cornea, iris ciliary body (ICB) or sclera at 37o C for 4 hours. Aliquots were quenched by the addition of acetonitrile and analyzed by HPLC. FP receptor binding was conducted using [3H]-Travoprost acid. Phosphoinositide turnover and intracellular Ca2+ mobilization were studied in HEK-293 cells expressing the cloned human ciliary body FP prostaglandin receptor. Results: Bimatoprost, the ethyl amide prodrug, was hydrolyzed to the potent FP agonist 17-Phenyl PGF2α by rabbit and human cornea, ICB and sclera. The rate of hydrolysis by human and rabbit cornea and ICB was similar. The rate of hydrolysis by the sclera was slower in humans than in rabbits. Both bimatoprost and 17-Phenyl PGF2α exhibited affinity for the FP receptor and both were agonists at the cloned human ocular FP receptor. Conclusion: Human and rabbit ocular tissues (cornea, ICB and sclera) convert bimatoprost to the potent prostaglandin FP agonist 17-Phenyl PGF2α . Bimatoprost and 17-Phenyl PGF2α are agonists at the human ocular FP receptor. These studies suggest that the ocular hypotensive effect of bimatoprost is due, at least in part, to its hydrolysis product, the potent FP prostaglandin agonist 17-Phenyl PGF2α .
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