In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives
Article first published online: 10 JUN 2010
© 2010 The Authors Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain
Journal of Pharmacy and Pharmacology
Special Issue: Recent advances in transdermal drug delivery
Volume 62, Issue 6, pages 756–761, June 2010
How to Cite
Legoabe, L. J., Breytenbach, J. C., N'Da, D. D. and Breytenbach, J. W. (2010), In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives. Journal of Pharmacy and Pharmacology, 62: 756–761. doi: 10.1211/jpp.62.06.0012
- Issue published online: 10 JUN 2010
- Article first published online: 10 JUN 2010
- Received September 30, 2009Accepted February 12, 2010
- in vitro;
- transdermal penetration
Objectives The aim of this study was to synthesise and determine the transdermal penetration of cytarabine alkylamide derivatives and assess the correlation of flux with physicochemical properties.
Methods The alkylamide derivatives of cytarabine were synthesised by acylation at the N4-amino group by the mixed anhydride method. The in-vitro permeation studies were performed using the Franz diffusion cell methodology. Furthermore, partition coefficients (n-octanol–water) and aqueous solubility of the N4-alkylamide derivatives of cytarabine were determined in order to obtain information about their lipophilicity and hydrophilicity.
Key findings The N4-alkylamides of cytarabine (acetyl, butanoyl, hexanoyl, octanoyl, and decanoyl derivatives) showed decreased hydrophilicity and increased lipophilicity. The log D values of the alkylamides were higher than that of the parent compound and increased linearly as the alkyl chain lengthened. N4-hexanoyl-4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl] pyrimidin-2-one) showed the highest median steady-state flux (Jss) of 89.0 nmol/cm2 per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm2 per h).
Conclusions The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine.