Approaches to the modeling of percutaneous absorption of drugs and drug effects

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The majority of pharmacokinetic models of percutaneous absorption describe linear systems of passive diffusion. Few models of the effects of drugs in the epidermis have been described except for in vivo measurements of skin surface temperature and blood flow. The goal of this research was to develop and apply pharmacokinetic study that describe nonlinear percutaneous absorption relationships and elucidate mechanisms for their behavior and to develop models that incorporate the effects of drugs in skin.

Models of four experimental systems were developed. The first three studies were in vitro percutaneous absorption systems with nonlinear dose-absorption relationships. The first study used an ionizable compound, benzoic acid, in which a dose related increase in the percentage of applied dose absorbed was observed. The second study examined the pharmacokinetics of metabolically saturating and nonsaturating doses of benzocaine.

The third study investigated the percutaneous absorption and barrier localization of a very lipophilic compound, phenylazophenol. Percutaneous absorption behavior was described in the first three studies by developing mechanistically illustrative models of their respective pharmacokinetic systems.

The pharmacokinetic models described: A system where physicochemical changes in the surface resulted in nonlinear absorption kinetics, A nonlinear pharmacokinetic system modulated by the metabolism of the drug in the viable tissue, and A metabolically active system in which the physicochemical properties of the viable tissue were rate limiting to diffusion of the parent compound.

The fourth study modeled a pharmacodynamic system of dexamethasone effects in viable epidermis. Using a perfusion apparatus, phosphorus nuclear magnetic resonance spectra were obtained of epidermis from which the actions of dexamethasone at different dose levels were determined. The data were used to fit an indirect model of pharmacodynamic action that was linked to a hypothetical pharmacokinetic study of dexamethasone percutaneous absorption as an initial attempt at cellular level cutaneous pharmacokinetic-pharmacodynamic modeling. The modeling techniques developed and described here are applicable to other topical and transdermal systems and also drug diffusion and action in other biological membranes.