The objective of this research is the development of a systematic approach to the design and optimization of prodrug based topical therapy. Prodrugs of the antiviral agent, 9-Beta-D-arabinofuranosyladenine (vidarabine, ara-A), with be investigated by means of a novel approach based upon concepts and techniques of physical chemistry which permit factoring out the various physical and biochemical processes influencing the delivery of the active form of the drug to the target sites. Transport and metabolism studies aimed at determining and/or predicting the target site concentrations of the vidarabine species for a variety of recently synthesized vidarabine prodrugs will be conducted. The studies will include experiments with the hairless mouse skin and the vaginal membrane of the guinea pig. The data analysis will involve the use of the recently developed methods of physical chemistry for handling the relatively complex problem of simultaneous diffusion and enzymatic reactions for a multi-component system in biological membranes and tissues. Additionally, flux dependence studies will be conducted with hairless mice and with guinea pigs to determine steady-state target tissue species concentration profiles and blood levels of the various vidarabine species for different prodrug delivery rates when vidarabine and its prodrugs are administered topically and when they are administered systemically. The data provided from the above will be compared to the results of flux/response studies on the efficacy of the prodrugs of ara-A in the topical treatment of herpes simplex virus (HSV) type 1 cutaneous infections in hairless mice and in the topical treatment of HSV type 2 genital infections in guinea pigs. The following outcomes from these studies are expected: (1) the differentiation between analog effects (the prodrug itself having an intrinsic effect) and prodrug effects (the prodrug serving as a precursor to the active species); (2) from infected animal studies with both topical and systemic administration, the determination of the locale to which the active moiety must be delivered to achieve its activity; and (3) based on (1) and (2), above, the determination of prodrug/delivery system combinations with optimal therapeutic activity.
