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DC Dahlin, MV W Bergamini, MA Curtis, TR Dean, CC Kiehlbauch, JE Chastain; Bimatoprost Hydrolysis to 17-phenyl PGF2 by Rabbit and Monkey Ocular Tissues, in vivo . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4109.
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Purpose: Bimatoprost is the ethyl amide of the potent prostaglandin FP agonist, 17-phenyl PGF2α. The in vivo hydrolysis of bimatoprost by ocular tissues was investigated in rabbits and monkeys following single topical ocular administration of bimatoprost. Methods: Male Dutch-Belted rabbits and Cynomolgus monkeys were administered a single 30-µL dose of a 0.03% bimatoprost ophthalmic solution (LUMIGAN®) into both eyes. Blood was sampled and animals euthanized at 0.5, 1, 2 and 4 hr post-dose, at which times ocular tissues (aqueous humor, iris-ciliary body and cornea) were collected. An LC/MS/MS method was used to measure bimatoprost and 17-phenyl PGF2α. Results: Hydrolysis of bimatoprost to 17-phenyl PGF2α occurred in both rabbit and monkey ocular tissues, in vivo. A species difference was observed with hydrolysis being substantially greater in rabbits than monkeys. In rabbits, virtually complete hydrolysis was observed, while in the monkey, levels of bimatoprost exceeded those for 17-phenyl PGF2α. Maximal mean concentrations (Cmax) of bimatoprost and 17-phenyl PGF2α in rabbits were, respectively, 5.07 ± 0.79 ng/g and 22.5 ± 2.2 ng/g in iris-ciliary body, and 0.939 ± 0.542 ng/mL and 42.3 ± 7.0 ng/mL in aqueous humor. Cmax in monkey aqueous humor was 10.0 ± 6.5 ng/mL for bimatoprost and 1.95 ± 1.39 ng/mL for 17-phenyl PGF2α, while Cmax levels in the cornea were 161 ± 91 ng/g and 25.5 ± 21.2 ng/g, respectively. Plasma concentrations of bimatoprost were quantifiable in the monkey, but not the rabbit, while 17-phenyl PGF2α levels were nonquantifiable in both species (quantitation limit: 0.1-0.2 ng/mL for bimatoprost and 0.5-1 ng/mL for 17-phenyl PGF2α. Conclusion: Bimatoprost was hydrolyzed to the potent FP agonist, 17-phenyl PGF2α in rabbit and monkey ocular tissues, in vivo. Hydrolysis was greater in rabbit than in monkey eyes but both produced pharmacologically relevant concentrations of 17-phenyl PGF2α.
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