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Proposed explanations include: Tissue retention of peptide or active metabolites Persistent activation of signaling cascades beyond peptide clearance Potential for active metabolites with prolonged tissue residence Excretion Pathways Limited data on elimination routes indicates: Likely renal excretion of peptide fragments based on molecular weight and water solubility Potential hepatic contribution to metabolite clearance No evidence of accumulation in chronic dosing studies in rats and monkeys Degradation products eliminated without evidence of toxic metabolite formation The dramatic disconnect between three-minute plasma half-life and prolonged metabolic effects remains one of the most intriguing and poorly understood aspects of AOD-9604 pharmacology, requiring further mechanistic investigation

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doi: 10.1001/archneurol.2010.227 116 DreherSIGrubbaPvon ToerneCMoruzziAMaurerJGojTet al