SELECTIVE COMPLEXING AGENTS DESIGNED AFTER ADENOSINE RECEPTOR AS PERCUTANEOUS PERMEATION ENHANCERS OF DRUGS

The objective was to evaluate selective complexing agents, naphthalene diamide diimide (I) and naphthalene diester diimide (II), as transpor t facilitators of adenosine across skin. Molecular modeling was used t o show favored binding, energetically and conformationally, between ad enosine and its selective complexing agents. The energy-minimized conf ormational structure of the adenosine-diamide diimide (I) complex indi cated favored binding conformationally and energetically by potential energy saving of 8.26 kcal/mol. Permeation studies of adenosine alone (control) and with the complexing agent were conducted across polydime thyl siloxane (PDMS), whole thickness human skin and isolated human st ratum corneum using vertical franz diffusion cells and infinite dose t echnique. Adenosine flux across PDMS was increased 10-fold by diester diimide (II) (0.28 mu g/min per cm(2) versus 0.027 mu g/min per cm(2) for the control). During permeation across whole thickness human skin, adenosine was primarily metabolized to inosine, which further metabol ized to hypoxanthine, and adenine was formed in small amounts by a min or pathway. The V-max and K-m values for adenosine metabolism were 6.7 x 10(-4) mM/min and 6.4 x 10(-3) mM, respectively. Thus, extensive me tabolism within the skin concurrent with diffusion prevented the estim ation of mass transfer rates of adenosine alone or in the presence of the complexing agent. Adenosine permeation across isolated stratum cor neum was not enhanced by diester diimide (II); however, increased amou nts of hypoxanthine and inosine were found in the receptor phase, indi cating enhanced uptake of adenosine. These results also suggested resi dual metabolic activity in the stratum corneum. A novel mechanism was demonstrated for permeation enhancement of drugs across lipophilic sol id-phase and biological membranes, using lipophilic selective complexi ng agents as transport facilitators. However, the inherent metabolic a ctivity of biological membranes profoundly influences drug transport a nd synthetic lipophilic membranes may therefore have limitations as mo dels of biological barriers. Copyright (C) 1996 Elsevier Science B.V.