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Terry Podoll, Suliman Al-Fayoumi, Elizabeth Prescott, Gang Sun, John W. Chandler, Ryo Kubota; Ocular Distribution of the Visual Cycle Modulator (VCM) 14C-ACU-4429 in Beagle Dogs. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5353.
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To evaluate the ocular distribution and characterize the pharmacokinetic profile of ACU-4429, a novel VCM, and its metabolites in beagle dogs after single and repeated oral doses.
Oral 14C-ACU-4429 0.3 mg/kg (40 μCi/kg/day) was administered as a single dose or repeated doses (once daily for 7 days) to a total of 36 male beagle dogs. Mass balance was assessed through 168 hours after a single dose or through 336 hours after the last repeated dose. Blood was collected at multiple timepoints up to 192 hours following the final dose; blood and plasma were analyzed for radioactivity and metabolic profiling. Ocular tissues were collected at multiple timepoints up to 168 hours after the final dose and analyzed for radioactivity (right eyes) or metabolic profiling (left eyes).
On average, 95% of the administered dose of radioactivity was recovered, including 46% in urine and 44% in feces. Radio-HPLC analyses detected 29 peaks of radioactivity in urine, 18 peaks in feces, and 38 peaks in plasma, indicating ACU-4429 was extensively metabolized after oral administration in dogs; overall, the parent compound accounted for <2% of radioactivity in excreta. In plasma, the fraction of parent compound relative to total radioactivity was <1%. The metabolic profile in plasma was qualitatively similar to that observed in completed rat and human radiolabel ADME studies. Among ocular tissues, the highest levels of radioactivity were present in melanin-containing tissues (iris-ciliary body, choroid, and RPE). Association of ACU-4429 with melanin was thought to be reversible, as radioactivity levels in these tissues declined over time. In RPE, Cmax of total radioactivity occurred at 12 hours post-dose, compared to 4 hours in plasma. In RPE, parent compound accounted for >90% of total radioactivity at all timepoints, and Cmax was 234-fold higher than in plasma (457 vs 1.95 ng•eq/g) after a single dose of 14C-ACU-4429.
In beagle dogs, orally administered 14C-ACU-4429 was preferentially distributed to melanin-containing ocular tissues, including RPE, the proposed site of action for ACU-4429. ACU-4429 exposure was markedly higher in RPE relative to plasma, supporting specific targeting of RPE by orally administered ACU-4429.
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