Antitumor agent, 5-diethylaminoethylamino-8-hydroxyimidazoacridinone, C-1311, (Symadex^R) developed in our laboratory , is under Phase II clinical trials. We showed earlier that C-1311 metabolism in vitro with rat liver microsomes led to four main metabolites [1]. However, the incubation of the studied compound with human E. coli recombinant cytochrome P450 isoenzymes (CYPs): 1A2, 2C9, 2C19, 2D6 and 3A4 did not result in significant amount of metabolic product [2]. Therefore, we suspected that cytochromes P-450 were not crucial enzymes involved in rat liver metabolism of Symadex^R. In order to elucidate the role of hepatic CYPs in metabolism of C-1311 we compared the elimination of the drug with blood and urine occurred in wild-type (WT) and hepatic NADPH: CYP oxidoreductase null-type (HRN^TM) mice. Mice were dosed at 50 mg/kg by ip injection, blood and urine samples were taken at 10, 20, 40, 60 minutes and 2, 4 and 6 hours and were analyzed by HPLC. Moreover, Metabolic transformations of C-1311 and its less active analog, C-1330 with liver microsomal fractions of HRN and WT mice were also compared. WT and HRN^TM mice liver microsomes were incubated with C-1311 and C-1330 and the obtained reaction mixtures were analyzed by HPLC with UV-vis or MS/MS detection. The results revealed slightly slower elimination of C–1311 in blood and urine of HRN^TM than of WT mice. In the presence of WT mice liver microsomes C-1311 was transformed to at least one product m/z 365 identified as C-1311 derivative with additional oxygen atom in aromatic ring and probably the second one, m/z 323, resulted from deethylation of the side chain. After incubation with HRN mice liver microsomes HPLC peaks of metabolites were lower. Similar relations between metabolite amounts with HRN and WT microsomes were found in the case of C-1330 compound. In addition, C-1330 turned out to be a prodrug of C-1311 as the metabolite m/z 351 equal to M+1 of C-1311 was found. In conclusion, the differences in elimination rates of C-1311 observed between HRN^TM and WT mice in blood and urine indicates that liver cytochromes P450 are involved in metabolism of Symadex to a small extent. If so, dealkylation of the side chain and some oxidative transformation of aromatic ring occur. However, extra-hepatic transformations of C-1311 may play a significant role.

[1] A.Wisniewska, A.Chrapkowska, A.Kot-Wasik, J.Konopa, Z.Mazerska, Metabolic transformations of antitumor imidazoacridinone, C-1311, with microsomal fractions of rat human liver enzymes, Acta Bioch.Polonica, 54, 831-838, (2007).
[2] A.Chrapkowska, E.Piatek, A.Wisniewska, J.Konopa, Z.Mazerska, The studies of imidazoacridinone antitumor agent, C-1311, in the field of metabolic transformations with cytochrome P450 isoenzymes, Abstracts of the 41^th meeting of the Polish Biochemical Society, Bialystok, September 2006, Acta Bioch.Polon. Vol 53, Suppl.1/2006, 83.

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