A Framework for Incorporating Transient Solute-Keratin Binding Into Dermal Absorption Models

Interpretation of experiments involving transient solute binding to isolated keratin substrates is analyzed and discussed in terms of their impact on transient permeation of topically-applied compounds through human stratum corneum. The analysis builds upon an earlier model (Nitsche and Frasch 2011 Chem Eng Sci 66:2019-41) by adding a second level of homogenization ( ultrascopic-to-microscopic) prior to the microscopic-to-macroscopic conversion. Here ultrascopic refers to isolated keratin suspensions, microscopic to corneocyte interiors and macroscopic to tissue-averaged properties in the stratum corneum. Results are interpreted in the context of current parameterizations of the underlying ultrascopic binding parameters. The present analysis, which is limited to linear binding isotherms common in dilute solutions, reveals a maximum in the macroscopic forward binding rate constant as a function of solute lipophilicity, whereas the underlying equilibrium constant increases monotonically and the macroscopic reverse binding rate constant decreases monotonically. The size and location of the maximum depends upon the hydration state of the stratum corneum. Explicit equations expressing these findings allow both equilibrium and kinetic binding data in isolated keratins to be applied to the kinetics of transient absorption through the skin. They will enable more quantitative estimation of the long-recognized stratum corneum reservoir function. (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

This study analyzes and discusses experiments involving the binding of transient solutes to isolated keratin substrates, and their impact on the transient permeation of compounds applied topically through the human stratum corneum. The analysis expands upon a previous model by adding a second level of homogenization and provides insights into the effects of solute lipophilicity on binding kinetics. The findings have implications for understanding and quantifying the reservoir function of the stratum corneum.