A pharmacokinetic model for the percutaneous absorption of indomethacin and the prediction of drug disposition kinetics.

A pharmacokinetic model with two parallel absorption processes from two fractions has been derived for the percutaneous absorption of indomethacin. The simulation includes five first-order rate constants assigned the following significance: (a) rapid absorption (ka1) and slow absorption (ka2) through the skin; and (b) distribution into the tissue and subsequent elimination from the body. The model, applied to data obtained after percutaneous dosing of ointments under occlusion, successfully described the plasma profile observed in the presence and absence of laurocapram (Azone) and sorbitan monooleate. The penetration characteristics through stripped skin were also well described by the model. It was clarified that indomethacin was absorbed via both pathways, with rapid and slow absorption rate constants at the initial time stage, and via the latter pathway at the later period. Also, laurocapram and sorbitan monooleate increased the fraction absorbed via the rapid absorption pathway by about three times, without a significant alteration of either absorption rate constant, while the enhancers gave no significant effect on either absorption pathway in the stripped skin. The results suggest that the model is simple yet adaptable enough to prove of general use for the interpretation of percutaneous absorption data.