Metabolism of the new liposomal anticancer drug N-4-octadecyl-1-beta-D-arabinofuranosylcytosine in mice

Metabolism and excretion of the new antitumor drug N-4-octadecyl-1-beta-D-a rabinofuranosylcytosine (NOAC) was investigated in mice. Mice were injected i.v. with tritium-labeled liposomal NOAC (4 mu mol/mouse). Analysis of HPL C-purified extracts of liver homogenates by liquid chromatography coupled w ith mass spectrometry revealed only the presence of unmetabolized drug. To study the excretion of the administered drug, mice were injected with triti um-labeled liposomal NOAC or as comparison with 1-beta-D-arabinofuranosylcy tosine (ara-C; 4 mu mol/mouse) and housed up to 48 h in metabolic cages. Ur ine and feces were collected at different time points and the kinetics of e xcreted radioactivity were determined, After 48 h, 39% of the injected [5-H -3]NOAC radioactivity was excreted in urine and 16% in feces, whereas ara-C radioactivity was only found in urine with 48% of the injected dose. Feces extracts and urine were purified by HPLC and radioactive fractions were fu rther analyzed by liquid chromatography coupled with mass spectrometry. The radioactivity of feces extracts of NOAC-treated mice was composed of unmet abolized NOAC, hydroxylated NOAC (NOAC + OH), its sulfated derivative (NOAC + OSO3H), and unidentified metabolites, whereas in urine, the hydrophilic molecules ara-C and ara-U were found. During the period of 48 h only 2% of the injected NOAC was eliminated in its unmetabolized form, whereas 25% was identified as main metabolite ara-C. Urine collected during 48 h in ara-C- treated mice contained 33% of the injected dose as unmetabolized drug and 1 3% as the main metabolite ara-U. Thus, NOAC is metabolized by two major pat hways, one leading to the hydrophilic metabolites ara-C and ara-U and the o ther to hydroxylated and sulfated NOAC.