@article {Mayr105, author = {Craig A. Mayr and Salah M. Sami and William A. Remers and Robert T. Dorr}, title = {Identification and Characterization of in VitroMetabolites of 2-[2'-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione (Azonafide)}, volume = {26}, number = {2}, pages = {105--109}, year = {1998}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Azonafide (2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de, h]isoquinoline-1,3-dione) is the parent of a new series of anthracene-containing antitumor agents. Its structure is based on amonafide but lacks a primary amine and has an anthracene chromophore rather than a naphthalene chromophore. Using a rat liver cytosol incubation and HPLC/MS detection, we have identified four metabolites resulting from in vitro metabolism of azonafide. These alkyl-modified derivatives include a mono- and a di-N'-desmethyl metabolite, anN'-oxide metabolite, and a carboxylic acid metabolite. Purified samples of these metabolites were analyzed for cytotoxic activity using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium vital dye (mitochondrial reductase) assay and for inhibition of topoisomerase II (TOPO II) using a cell-free enzymatic system. Each metabolite had decreased cytotoxicity relative to azonafide with the following relative potencies in descending order: the mono-N'-desmethyl metabolite, di-N'-desmethyl metabolite, the N-oxide metabolite, and the carboxylic acid metabolite. Similarly, the N'-desmethyl metabolites retained TOPO II inhibitory activity but with lower potency than azonafide. The N-oxide and carboxylic acid metabolites did not inhibit TOPO II at 0.05 and 0.5 μg/ml, respectively. Thus, metabolism of azonafide by rat liver cytosol represents a detoxification pathway rather than a bioactivation scheme for this DNA intercalator. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/26/2/105}, eprint = {https://dmd.aspetjournals.org/content/26/2/105.full.pdf}, journal = {Drug Metabolism and Disposition} }