TY - JOUR T1 - Rapid Distribution of Liposomal Short-Chain Ceramide in Vitro and in Vivo JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1709 LP - 1715 DO - 10.1124/dmd.107.019679 VL - 36 IS - 8 AU - Banu S. Zolnik AU - Stephan T. Stern AU - James M. Kaiser AU - Yasser Heakal AU - Jeffrey D. Clogston AU - Mark Kester AU - Scott E. McNeil Y1 - 2008/08/01 UR - http://dmd.aspetjournals.org/content/36/8/1709.abstract N2 - Ceramide, an endogenous sphingolipid, has demonstrated antieoplastic activity in vitro and in vivo. However, the chemotherapeutic utility of ceramide is limited because of its insolubility. To increase the solubility of ceramide, liposomal delivery systems have been used. The objective of the present study was to characterize the pharmacokinetics and tissue distribution of C6-ceramide and control (non-C6-ceramide) nanoliposomes in rats, using [14C]C6-ceramide and [3H]distearylphosphatidylcholine (DSPC) as tracers of the ceramide and liposome components, respectively. Ceramide liposomes were administered at 50 mg of liposomes/kg by jugular vein to female Sprague-Dawley rats. The apparent volume of distribution (Vd) of [3H]DSPC was approximately 50 ml/kg, suggesting that the liposomes were confined to the systemic circulation. In contrast, the Vd of [14C]C6-ceramide was 20-fold greater than that of liposomes, indicating extensive tissue distribution. This high Vd of [14C]C6-ceramide in relation to that of [3H]DSPC suggests that ceramide and liposomes distribute independently of each other. This disparate disposition was confirmed by tissue distribution studies, in which [14C]C6-ceramide exhibited rapid tissue accumulation compared with to [3H]DSPC. Examination of ceramide liposome blood compartmentalization in vitro also demonstrated divergent partitioning, with liposomes being confined to the plasma fraction and ceramide rapidly equilibrating between red blood cell and plasma fractions. A bilayer exchange mechanism for ceramide transfer is proposed to explain the results of the present study, as well as give insight into the documented antineoplastic efficacy of short-chain ceramide liposomes. Our studies suggest that this nanoscale PEGylated drug delivery system for short-chain ceramide offers rapid tissue distribution without adverse effects for a neoplastic-selective, insoluble agent. The American Society for Pharmacology and Experimental Therapeutics ER -