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Carrie C Murray, Adam Brockman, David Albers, William K McVicar; Quantitative Ocular and Whole-Body Autoradiography Following a Single Topical Ocular Administration of Trabodenoson to Rabbits. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4593.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the ocular and systemic distribution and pharmacokinetics of trabodenoson in pigmented rabbits following a single topical ocular instillation.
A single drop of radiolabeled trabodenoson (14C-INO-8875) was instilled in the left eye (40 µl; 0.8 mg/eye) of Dutch-Belted rabbits (1.5-2 kg; age 5-6 mths). Animals were monitored daily, and blood, urine, and feces was collected 0-4 hrs, 4-8 hrs, 8-24 hrs, and at 24 hr intervals thereafter through 168 hours post-dose. Radioactivity levels in all samples were measured by liquid scintillation counters. Additionally, levels of parent compound as well as up to nine metabolites were quantified by radio-HPLC. Quantitative autoradiography was performed on whole body as well as on selected systemic and ocular tissues at various timepoints from 0.25 through 96 hrs post dose.
Following single drop instillation, 14C-INO-8875 widely and rapidly distributed within the eye with concentrations (ng equilavents) within the anterior globe reaching peak levels 30 min post-dose. Concentrations declined thereafter, but were still detectable at 168 hrs post-dose. Systemically, the highest concentrations were observed within nasolacrimal duct, gastrointestinal organs, kidney, liver, gall bladder and urine. This distribution reflects a fraction of dosed material entered the nasal passage and oral cavity, while some labeled material entered into systemic circulation. Little to no radiolabeled material was detected in the brain indicating minimal penetration through the blood-brain barrier. Metabolically, INO-8875 appears to be rapidly metabolized following topical ocular administration and is primarily cleared via hepatic and renal elimination routes.
Trabodenoson rapidly distributes within the eye following topical ocular instillation. These findings coupled with an overall low systemic exposure and rapid clearance provide a favorable safety and pharmacodynamic profile.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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