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Drug Metabolism and Disposition Fast Forward
First published on May 19, 2008; DOI: 10.1124/dmd.107.019679

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Received for publication November 7, 2007.
Revised May 13, 2008.
Accepted for publication May 15, 2008.

Rapid Distribution of Liposomal Short-Chain Ceramide In Vitro and In Vivo

Banu S. Zolnik 1, Stephan T. Stern 1*, James M. Kaiser 2, Yasser Heakal 2, Jeffery D. Clogston 1, Mark Kester 2, Scott E. McNeil 1

1 National Cancer Institute 2 Penn State College of Medicine

* Address correspondence to: E-mail: sternstephan{at}mail.nih.gov

Abstract

Ceramide, an endogenous sphingolipid, has demonstrated antineoplastic activity in vitro and in vivo. However, the chemotherapeutic utility of ceramide is limited, due to its insolubility. To increase the solubility of ceramide, liposomal delivery systems have been utilized. 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]-DSPC (distearylphosphatidylcholine) as tracers of the ceramide and liposome components, respectively. Ceramide liposomes were administered at 50 mg liposome/kg by jugular vein to female S.D. rats. The apparent volume of distribution (Vd) of [3H]-DSPC was 50 mL/kg, suggesting that liposome was confined to the systemic circulation. By contrast, the Vd of [14C]-C6-ceramide was 20-fold greater than that of liposome, indicating extensive tissue distribution. This high Vd of [14C]-C6-ceramide in relation to [3H]-DSPC suggests that ceramide and liposome distribute independently of each other. This disparate disposition was confirmed by tissue distribution studies, in which [14C]-C6-ceramide exhibited rapid tissue accumulation in comparison to [3H]-DSPC. Examination of ceramide liposome blood compartmentalization in vitro also demonstrated divergent partitioning, with liposome 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 anti-neoplastic efficacy of short-chain ceramide liposomes. Our studies suggest that this nanoscale PEG'ylated drug delivery system for short-chain ceramide offers rapid tissue distribution without adverse effects for a neoplastic-selective, insoluble agent.


Key words: anticancer agents, liposomal drug delivery, pharmacokinetics




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