Numerically generated substrate concentration profiles within the tissue and resulting substrate fluxes through the tissue are presented for various values of the diffusion coefficient, substrate partition coefficient, tissue thickness and maximum metabolic rate to illustrate their relative effect on the overall kinetics of drug permeation. The results of the numerical computations and theoretical derivations demonstrate that all of the parameters have an influence on the permeation and concurrent metabolism of intact substrate, tissue thickness having the strongest effect. The ratio of the Michaelis constant Km to the drug concentration in the first layer of the tissue will also influence the extent of metabolism. Parameters used for those calculations were validated in independent experiments.
Experimental data are in good agreement with the numerical predictions.
It is shown theoretically and experimentally that the viable epidermis can represent an effective metabolic barrier to block the permeation of labile drugs. The physical model may be helpful to understand this barrier and the complex processes involved. It also provides a rational basis for implications to dermal and transdermal drug delivery.