Ammoxetine Hydrochloride

Given the high prevalence of polypharmacy among patients with depression, this study systematically assesses the drug-drug interaction (DDI) risks of the investigational antidepressant ammoxetine (AMT) mediated by cytochrome P450 2D6 (CYP2D6) (metabolic enzyme) and multidrug and toxin extrusion protein 1 (MATE1) (renal transporter), and characterizes the resulting metabolism-transport interaction cascade. In vitro DDI risk screening for AMT was performed using human liver microsomes, recombinant CYP enzymes, and transporter-overexpressing cell lines. Static mechanistic models were used to predict human DDI risks, with sensitivity analyses incorporated to assess CYP2D6 poor metabolizers (PMs). Finally, in vivo validation was carried out in Institute of Cancer Research mice, humanized liver mice, and Sprague-Dawley rats. AMT was identified as a dual substrate and a reversible inhibitor of CYP2D6. Quinidine inhibition of CYP2D6-mediated AMT metabolism showed marked species differences (IC_{50, human} < IC_{50, mouse}). AMT inhibited MATE1 with an IC₅₀ of 18.75 μM, with no significant activity against MATE2-K/organic cation transporter 1/2. In humanized liver mice, quinidine coadministration increased AMT exposure (AUCR_obs = 2.87); in rats, AMT coadministration elevated metformin (MATE1 substrate) area under the curve by 68%. Static models predicted that CYP2D6 PMs may have 5- to 10-fold higher AMT exposure, amplifying MATE1 inhibition to increase metformin area under the curve ratio (AUCR) to 2.5-4.1. Coadministration of quinidine was projected to increase metformin AUCR to 2.2. AMT clinical development requires rigorous assessment of the elevated systemic exposure when coadministered with potent CYP2D6 inhibitors. Coadministration with MATE1 substrates (eg, metformin) may delay AMT renal excretion, with superimposed metabolism-transport DDIs posing heightened risk in patients with CYP2D6 PMs or renally impaired. This study highlights the importance of integrating metabolic and transporter pathways for comprehensive DDI risk assessment. SIGNIFICANCE STATEMENT: This study reveals that the novel antidepressant ammoxetine poses dual drug interaction risks as a cytochrome P450 2D6 (CYP2D6) substrate/inhibitor affecting metabolism and a multidrug and toxin extrusion protein 1 inhibitor impairing renal excretion. Using humanized models and static mechanistic models, the interactions were validate in vivo and characterize the proposed metabolism-transport interaction cascade, delineating clinically relevant risks, including amplified ammoxetine exposure with strong CYP2D6 inhibition and heightened vulnerability in CYP2D6 poor metabolizers.