A pharmacokinetic model for percutaneous absorption of valproic acid and prediction of drug disposition.

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Abstract
To predict the plasma concentrations after percutaneous application of valproic acid (VPA), we presented a new pharmacokinetic model which includes simultaneous two absorption processes through the skin. The simulation contains four first-order rate constants for the following: a) absorption via the lipid and water routes in skin and b) uptake from the skin into systemic circulation and subsequent elimination. The fitness of the model presented for experimental data was compared with simple one-compartment models. As a result, the new model was successfully able to describe the time course of the plasma VPA concentrations following percutaneous application of the ointments. VPA was found to be rapidly absorbed across the water routes (kal = 2.60 h-1), which accounted for about 70% of the total, followed by a lasting absorption via the lipid routes (ka2=0.108 h-1). The pharmacokinetic model with parallel lipid and aqueous pore skin transport pathways in skin was more adequate for the interpretation of p.c. absorption data of VPA than the models with an absorption process.