Physiologically Relevant One-Compartment Pharmacokinetic Models for Skin. 2. Comparison of Models when Combined with a Systemic Pharmacokinetic Model

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Abstract
Transport of chemicals through skin is best modeled as passive diffusion through a membrane, but mathematical solutions for realistic conditions are cumbersome. Compartment models, representing skin as a stirred tank, are mathematically simpler but less physiologically relevant. In a previous paper, several different compartment models were developed assuming constant blood and vehicle concentrations. Here, five skin models (four of the previously described compartment models and one membrane model) are combined with a one-compartment systemic pharmacokinetic (PK) model to examine the effects of changing vehicle and blood concentrations and to clarify how differences between skin models affect the predicted systemic response. The skin-PK models were solved with the same input parameters (i.e., permeability coefficients, partition coefficients, skin thickness, and cutaneous blood flow rates) and compared for five different exposure scenarios. Because the models have different underlying assumptions, they do predict different results. For many exposure situations compartment models give acceptable results, with the most pronounced differences from the membrane model during short exposure times. Generally, the compartment model that most closely represents the membrane model was developed by forcing it to match the membrane model for conditions similar to those of the given exposure scenario.