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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 (J(ss)) of 89.0 nmol/cm(2) per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm(2) per h)., Conclusions: The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine.

The purpose of this study was to synthesize and determine the in vitro transdermal penetration of cytarabine and its 5'-alkyl esters and to establish a correlation, if any, with selected physicochemical properties. The n-alkyl esters were synthesized by acylation of cytarabine (1) at its pharmacophoric 5'-OH. The transdermal flux values of (1) and its esters were determined in vitro using Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation to transdermal flux. An inverse relation was observed between the water solubility (Sw) and log D values. Of all esters, (4) exhibited the highest flux value of 22.2 nmol x cm(-2) x h(-1), which is significantly different to that of the parent drug cytarabine (3.70 nmol x cm(-)2 x h(-1)). No trend was found between water solubility and flux values.