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Y. Horibe, S. Fujii, K. Kawazu; Ocular Tissue Distribution of Olmesartan, a Selective Angiotensin II Type 1 Receptor Antagonist, Following Administration of a Single Ocular Dose to Cynomolgus Monkeys . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5376.
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Purpose: Olmesartan, a selective angiotensin II type 1 receptor antagonist, is under clinical development as an ocular hypotensive drug. We examined the ocular tissue distribution of olmesartan following administration of a single ocular dose to cynomolgus monkeys. Methods: Fourteen monkeys were dosed in each eye with 4%14C–Olmesartan ophthalmic solution at a target dose level of 800 µg/eye. After dosing, concentrations of radioactivity (ng equivalents 14C–Olmesartan/g) were determined in ocular tissues and plasma (selected time points: 0.5, 1, 2, 4, 8, 12, and 24 hours postdose). Selected aqueous humor and plasma samples were profiled for metabolites. Results: Almost all ocular tissues reached the maximum concentrations (Cmax) by 2 hours postdose, which then steadily declined through 24 hours postdose. Two hours postdose, the following rank order of concentration in the tissues was obtained: cornea (6,090) > conjunctiva (bulbar, 3,270) > anterior sclera (2,340) > ciliary body (including the ciliary muscle, 279) > iris (234) > aqueous humor (207) > posterior sclera (199) > retina + choroid (50.8) > optic nerve (15.7). Levels of concentrations in plasma were lower compared to ocular tissues, 28.7 at 0.5 hours (Cmax) and 7.39 at 2 hours postdose, respectively. The majority of the radioactivity in aqueous humor and plasma was associated with unchanged parent drug. Conclusions: Following ocular administration, 14C–Olmesartan was rapidly absorbed into ocular tissues and systemic circulation. The majority of the radioactivity was detected in the anterior parts of the eye including the ciliary body which is considered as a target tissue of olmesartan, an ocular hypotensive drug. The radioactivity was also observed in the posterior tissues, suggesting that 14C–Olmesartan penetrated to the posterior parts of the eye after instillation.
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