Nuclease-mediated metabolism

Administration is by direct injection of 0.05 ml product into the eye (intravitreal injection), initially once every 2 weeks and subsequently once every 4 weeks. Animal studies (rabbits) indicated that the product is cleared from the eye over the course of 7-10 days, with direct nuclease-mediated metabolism representing the primary route of elimination. The most commonly observed side effect is ocular inflammation, which typically occurs in one in every four patients. 

Long tissue elimination half-life cleared by nuclease-mediated metabolism. 

As discussed in Section 4.2.3, the elimination of 2 -MOE partially modified AS Os is attributed to slow (but continuous) nuclease-mediated metabolism in tissue, followed by ultimate excretion of these shortened metabolites in the urine. This major elimination pathway for 2 -MOE partially modified AS Os is shown graphically in Fig. 4.9, where approximately 75% of the total radiolabeled dose is excreted in the urine by 90 days after a single dose (5 mg/kg) of [3H]-ISIS 104838 to rats [26]. Another example of the ultimate elimination of this class of compound via slow metabolism in tissues, followed by the urinary excretion of metabolites, is the mass-balance study with [3H]-labeled ISIS 113715. Here, between 8% and 37 % of administered dose was excreted within the first 24 h, followed by a daily ur-... 

PONs are cleared from tissues by nuclease-mediated metabolism, with half-lives that vary between 20 and 120 h, depending on the organ or tissue. Successive removal of bases from the 3 -end is the major metabolic pathway in plasma, while both 3 and 5 exonuclease excision may occur in tissues. Exonuclease metabolism in plasma and tissues is... 

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