1988 Volume 36 Issue 10 Pages 4060-4067
A lipophilic prodrug of 1-β-D-arabinofuranosylcytosine (Ara-C), N4-[N-(cholesteryloxycarbonyl) glycyl]-Ara-C (COCG-Ara-C) was entrapped in unilamellar liposomes or solubilized in pH 7.4 phosphate-buffered saline with hydrogenated castor oil polyethylene glycol ether (HCO-60), and its biological disposition was studied in mice. Regardless of dosage form, COCG-Ara-C was accumulated in the liver after intravenous (i.v.) injection, but not in the lung or kidney. In contrast, the blood clearance and spleen distribution of COCG-Ara-C varied with dosage form: slow blood clearance and increased spleen levels of the prodrug were observed for the liposome-entrapped form relative to the detergent-solubilized form. Both COCG-Ara-C preparations successfully maintained the plasma levels of Ara-C compared with Ara-C aqueous solution. However, the plasma Ara-C concentration time profiles were markedly different between the preparations. After i.v. injection of liposome-entrapped COCG-Ara-C, plasma Ara-C levels increased slowly for the first 16h and subsequently decreased gradually. On the other hand, rapid appearance of Ara-C in the circulation and subsequently gradual elimination were observed after injection of the detergent-solubilized prodrug. The relative bioavailabilities obtained with respect to Ara-C aqueous solution were 592% and 129% for the liposome-entrapped and detergent-solubilized forms, respectively. The extremely high bioavailability of liposome-entrapped COCG-Ara-C could be explained in part by the finding that the liposome-entrapped prodrug reduced the plasma clearance of the parent drug Ara-C. These results indicate the potential utility of COCG-Ara-C-bearing liposomes as a sustained-release delivery system of Ara-C applied by i.v. injection.
