Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice.

Abstract

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-N-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model. In the present study, we report that SQdFdC nanoassemblies triggered controlled and prolonged release of dFdC and displayed considerably greater t(1/2) (approximately 3.9-fold), mean residence time (approximately 7.5-fold) compared with the dFdC administered as a free drug in mice. It was also observed that the linkage of gemcitabine to the 1,1',2-trisnorsqualenic acid noticeably delayed the metabolism of dFdC into its inactive difluorodeoxyuridine (dFdU) metabolite, compared with dFdC. Additionally, the elimination of SQdFdC nanoassemblies was considerably lower compared with free dFdC, as indicated by lower radioactivity found in urine and kidneys, in accordance with the plasmatic concentrations of dFdU. SQdFdC nanoassemblies also underwent considerably higher distribution to the organs of the reticuloendothelial system, such as spleen and liver (p < 0.05), both after single- or multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights that may explain the previously observed greater efficacy of SQdFdC nanoassemblies against experimental leukemia.

• Authors: L Harivardhan Reddy, Hania Khoury, Angelo Paci, Alain Deroussent, Humberto Ferreira, Catherine Dubernet, Xavier Declèves, Madeleine Besnard, Helène Chacun, Sinda Lepêtre-Mouelhi, Didier Desmaële, Bernard Rousseau, Christelle Laugier, Jean-Christophe Cintrat, Gilles Vassal, Patrick Couvreur
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 36 Issue 8 Pg. 1570-7 (Aug 2008) ISSN: 1521-009X [Electronic] United States
• PMID: 18474674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Deoxycytidine
• Squalene
• Gemcitabine

Topics

• Animals
• Antineoplastic Agents (blood, metabolism, pharmacokinetics)
• Chromatography, Liquid
• Deoxycytidine (analogs & derivatives, blood, metabolism, pharmacokinetics)
• Female
• Magnetic Resonance Spectroscopy
• Mice
• Mice, Inbred DBA
• Squalene (metabolism)
• Tandem Mass Spectrometry
• Tissue Distribution
• Gemcitabine