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Terry Podoll, Suliman Al-Fayoumi, Elizabeth Prescott, John Chandler, Ryo Kubota; Comparative Ocular Tissue Distribution Kinetics of the Visual Cycle Modulator (VCM) Emixustat-HCl in Rats, Beagle Dogs, and Cynomolgus Monkeys. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4615.
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Ocular distribution studies using 14C-emixustat-HCl were undertaken in rat, dog, and monkey to better understand the time-course of emixustat ocular tissue exposure in relation to observed pharmacologic activity in animal models.
Pigmented and albino rats received single oral doses of 1 mg/kg, or a repeated oral dose (once daily [QD] for 7 days). Dogs received 0.3 mg/kg as a single or a repeated oral dose (QD for 7 days). Monkeys received 0.9 mg/kg/day as a single or a repeated oral dose (0.3 mg three times daily for 7 days). Selected ocular tissues were collected and analyzed for radioactivity (right eyes) or metabolic profiling (left eyes) for up to six weeks postdose.
On average, 96% of the administered dose of radioactivity was recovered in excreta in all studies within one week of the last dose. Radio-HPLC analyses detected 25 - 50 peaks of radioactivity in urine, 15 - 39 peaks in feces, and 27 - 58 peaks in plasma. The parent compound accounted for <3% of radioactivity in excreta and ≤ 10% in plasma, indicating emixustat was extensively metabolized. The metabolic profile in plasma was qualitatively similar between species and to that observed in a completed human radiolabeled ADME study. In contrast to plasma and excreta, analysis of the ocular tissues of rat, dog, and monkey demonstrated that the amount of parent compound was higher than metabolites. Parent compound accounted for >70% of total radioactivity at peak levels in iris-ciliary body, choroid, and retinal pigmented epithelium (RPE) in the dog and monkey, and was also the largest component in the rat at 35% of the radioactivity. Peak levels of total radioactivity in these tissues occurred at 12 hours after the last dose, compared to 4 hours postdose in plasma.
In rats, dogs, and monkeys, orally administered 14C-emixustat-HCl was preferentially distributed to iris-ciliary body, choroid, and RPE, the proposed site of VCM action. Emixustat exposure was markedly higher in the eye relative to plasma in all three species, despite extensive systemic metabolism of the parent molecule.
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