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Abstract #47664 Published in IGR 13-4
Ocular and systemic distribution of ino-8875, a selective adenosine A1 receptor agonist, in rabbits by quantitative whole body autoradiography (QWBA) and tissue analysis
Prescott E; Struble C; Denissen J; Kim NDrug Metabolism Reviews 2011; 43: 78-79
INO-8875, a highly selective adenosine A1 receptor agonist, is under development for the treatment of ocular hypertension and primary open-angle glaucoma. INO-8875 lowers intraocular pressure (IOP) by increasing conventional outflow facility via the trabecular meshwork (TM). The ocular and systemic tissue distribution of INO-8875 was evaluated in New Zealand White and Dutch-Belted rabbits after topical ocular administration. Ocular and systemic tissue distribution and mass balance were studied using [(14)C]-INO-8875. Following topical ocular administration, the radioactivity was distributed in the anterior globe of the eye (cornea, aqueous humor, trabecular meshwork, and ciliary body) and systemic tissues at 0.25 hours post-dose, with greatest ocular exposure in the cornea, without melanin binding. Nasolacrimal drainage was significant and resulted in levels of [(14)C]-INO-8875-related material being distributed through the whole body. Significant levels of radioactivity were observed in the kidney and liver, suggesting both hepatic and renal clearance. The percentage of dose in the ocular and systemic tissues was calculated based upon tissue weights for the New Zealand White rabbit. The route of distribution of (14)C]INO-8875 is thought to be typical of an ocular drug following topical ocular administration. Nasolacrimal drainage can be an important factor in the systemic distribution of a topical ocular compound. The percentage of dose administered found in the ocular tissues and systemic tissues also demonstrates the percentage of drug that is absorbed into the eye and drained into the whole body. The long-lasting drug concentrations in ocular target tissues with low systemic exposure and rapid clearance suggest a favorable safety profile and therapeutic index for INO8875.
E. Prescott. Drug Metabolism Department Covance, Madison, United States.
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
