Percutaneous absorption in man: A kinetic approach

A biophysically based kinetic model of chemical absorption via human skin was developed and applied to the penetration kinetics of 12 chemicals: aspirin, benzoic acid, benzyl nicotinate, caffeine, chloramphenicol, colchicine, dinitrochlorobenzene, diethyltoluamide, malathion, methyl nicotinate, nitrobenzene, and salicylic acid. The pharmacokinetic model is linear and includes four first-order rate constants: (1) k₁ describes penetrant diffusion through the stratum corneum; (2) k₂ relates to further transport across the viable epidermal tissue to the cutaneous blood vessels; (3) k₃ is a parameter which delays the partitioning of penetrant at the stratum corneum-viable tissue interface and, in conjunction with k₂, reflects the penetrant's relative affinity for the stratum corneum over the viable tissue; and (4) k₄ characterizes the elimination rate of chemical from blood to urine. Previously determined diffusion coefficients and molecular weight corrections were used to estimate k₁ and k₂; k₄ values employed were those measured experimentally. Urinary excretion rate data following topical administration were simulated and k₃ was estimated for each penetrant by optimizing the fit of the model to the data points. Ratios of k₃ k₂ should be related to the partition coefficients for the chemicals between stratum corneum and viable tissue and it was shown that these ratios agreed reasonably well with the corresponding octanol-water partition coefficients. This approach may have potential for predicting the general percutaneous absorption kinetics of chemicals based on recognized cutaneous biology and penetrant molecular weight and lipophilicity.