Theoretical design of prodrug-enhancer combination based on a skin diffusion model: prediction of permeation of acyclovir prodrugs treated with 1-geranylazacycloheptan-2-one.
OBJECTIVE
A theoretical design of percutaneous penetration enhancement in which prodrug derivation and enhancer application are combined is proposed based on the skin diffusion model and it is experimentally verified.


METHODS
Employing acyclovir as a model drug, the hypothesis was tested by synthesis of its prodrugs and evaluation of their in vitro permeation in the rat skin, with or without a penetration enhancer, 1-geranylazacycloheptan-2-one(GACH).


RESULTS
Among five acyclovir prodrugs, those with higher lipophilicities (propionate, butyrate, valerate, and hexanoate prodrugs) showed greater skin penetration than those of hydrophilic prodrugs (acetate), when administered in combination with GACH. Furthermore, the observed enhancement ratios were in good agreement with those predicted by theoretical consideration.


CONCLUSIONS
Thus, skin permeation of prodrugs applied with an enhancer can be predicted and optimized by model analysis.
Bando
H
H
Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Takagi
T
T
Yamashita
F
F
Takakura
Y
Y
Hashida
M
M
D000212:Acyclovir / Q000493:pharmacokinetics*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption / Q000187:drug effects*
D001381:Azepines; D011355:Prodrugs; C068207:1-geranylazacycloheptan-2-one; D000212:Acyclovir