In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives.
OBJECTIVE
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.


RESULTS
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.
Legoabe
Lesetja J
LJ
Unit for Drug Research and Development, North-West University, Potchefstroom, South Africa. lesetja.legoabe@nwu.ac.za
Breytenbach
Jaco C
JC
N'Da
David D
DD
Breytenbach
J Wilma
JW
D000279:Administration, Cutaneous; D000328:Adult; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D003561:Cytarabine / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D010539:Permeability; D011355:Prodrugs; D012869:Skin Absorption; D012995:Solubility; D013329:Structure-Activity Relationship
D000577:Amides; D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003561:Cytarabine