RT Journal Article SR Electronic T1 Metabolism of the New Liposomal Anticancer Drug N4-Octadecyl-1-β-D-Arabinofuranosylcytosine in Mice JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 342 OP 350 VO 27 IS 3 A1 Sibylle K. M. Koller-Lucae A1 Marc J.-F. Suter A1 Katharina M. Rentsch A1 Herbert Schott A1 Reto A. Schwendener YR 1999 UL http://dmd.aspetjournals.org/content/27/3/342.abstract AB Metabolism and excretion of the new antitumor drug N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC) was investigated in mice. Mice were injected i.v. with tritium-labeled liposomal NOAC (4 μmol/mouse). Analysis of HPLC-purified extracts of liver homogenates by liquid chromatography coupled with mass spectrometry revealed only the presence of unmetabolized drug. To study the excretion of the administered drug, mice were injected with tritium-labeled liposomal NOAC or as comparison with 1-β-d-arabinofuranosylcytosine (ara-C; 4 μmol/mouse) and housed up to 48 h in metabolic cages. Urine and feces were collected at different time points and the kinetics of excreted radioactivity were determined. After 48 h, 39% of the injected [5-3H]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 further analyzed by liquid chromatography coupled with mass spectrometry. The radioactivity of feces extracts of NOAC-treated mice was composed of unmetabolized 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 13% as the main metabolite ara-U. Thus, NOAC is metabolized by two major pathways, one leading to the hydrophilic metabolites ara-C and ara-U and the other to hydroxylated and sulfated NOAC. The American Society for Pharmacology and Experimental Therapeutics