Modeling of diffusion and concurrent metabolism in cutaneous tissue

Area of Science:

• Pharmacokinetics
• Biophysics
• Dermatology

Background:

• Cutaneous metabolism is crucial for limiting xenobiotic absorption.
• Understanding drug diffusion and metabolism in skin is vital for therapeutic and environmental exposure assessments.

Purpose of the Study:

• To develop and validate a physical model for Fickian diffusion and Michaelis-Menten metabolism in human epidermis.
• To investigate the impact of various parameters on drug permeation through metabolizing skin tissue.

Main Methods:

• Numerical simulation of substrate concentration profiles and fluxes within metabolizing skin.
• Validation of the model using permeation and metabolism data of L-Ala-4-methoxy-2-naphthylamide (Ala-MNA) across human skin and HaCaT cells.
• Comparison of experimental results with numerical predictions.

Main Results:

• The physical model demonstrated excellent agreement between numerical predictions and experimental data.
• Tissue thickness (L) was identified as the most influential parameter affecting drug permeation.
• The dimensionless coefficient 2 alpha effectively estimates concentration gradients and metabolic extent, predicting minimal Ala-MNA permeation through intact human skin.

Conclusions:

• The developed physical model is a valid tool for predicting drug diffusion and metabolism in the epidermis.
• The model highlights the significant role of skin thickness in limiting xenobiotic penetration.
• This approach has potential applications for other metabolizing biological tissues.