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Yann Quentric, Thierry Amar, Nathalie Barre, Laurence FERAILLE, Raouf Rekik; Ocular Pharmacokinetic Study Comparing Ramipril and Ramiprilat Formulations Administered Orally or Topically in Pigmented Rabbits.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2360.
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The aim of this study was to determine ramiprilat bioavailability and to compare the systemic exposure of ramiprilat administered once either topically or as ramipril per os in rabbit.
Ninety pigmented rabbits were randomized into three groups of thirty animals and divided into six time-point subgroups. All animals received a single 35-µL topical administration of ramiprilat 2% in both eyes or a single oral administration of ramipril (0.6 mg/kg). Plasma, cornea, aqueous humor, vitreous, retina, choroid and sclera were sampled at 0.5, 1, 2, 4, 8 and 24 h after administration. Content of ramipril (only for oral administration group) and ramiprilat was determined in sampled ocular specimens and plasma.
Following a single topical administration of ramiprilat 2% or a single oral administration of ramipril at 0.6 mg/kg in rabbits, all animals showed a normal body weight gain during the course of the study. No ramipril or ramiprilat was quantifiable in cornea, aqueous humor, vitreous, retina and sclera from animal orally dosed with ramipril. Level of ramiprilat was only quantified in choroid. After a single topical administration of ramiprilat 2%, high level of ramiprilat was found in cornea and aqueous humor. The peak was observed 1 h after the instillation and declined by 4 to 8 h. Gradual level of ramiprilat was found in posterior ocular structures with high level in sclera than progressively less in choroid, retina and vitreous. The peak was observed 1 h after the instillation and declined by 8 to 24 h. Systemic exposure to ramiprilat was higher after oral administration than after instillations. The peak was observed 4 h after both routes of administration and declined by 24 h for the oral administration.
Following a single topical administration of ramiprilat 2% in both eyes or single oral administration of ramipril at 0.6 mg/kg in rabbits, it can be stated that instillation of ramiprilat 2% delivered higher levels of ramiprilat to the ocular structures than oral administration with lesser systemic exposure. The transient presence of ramiprilat in the sclera after instillation suggests that early delivery of topically dosed ramiprilat to the posterior segment followed a trans-scleral route. The systemic passage contributed to the late delivery of ramiprilat to the choroid.
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