Are lateral lipid-phase diffusion coefficients pertinent to dermal absorption?

The skin's outer barrier layer, the stratum corneum (SC), is comprised of keratin-rich corneocytes, connected by proteinaceous corneodesmosomes and separated by nonpolar, lamellar lipids. The lipids are inherently anisotropic due to their lamellar organization. There is growing acceptance that this structural anisotropy carries over into transport properties including diffusive mass transport, which is consequently characterized by two diffusion coefficients, D‖lipfor lateral diffusion along the lipid lamellae and D⊥lipfor transverse diffusion across them. Many microscopic models of SC transport have focused on D‖lip, as it is easier to measure and intuitively important if one considers the intervening corneocytes to be impermeable "bricks." However, the latter concept crumbles under close observation, and the weight of evidence shows that the corneocyte phase of the SC is considerably more permeable to most solutes than are the intercellular lipids. Given this finding and a plausible organization of the SC lipids at corneocyte boundaries, the ratio D⊥lip/D‖lip determines the balance of transcellular versus intercellular diffusion. Based on a detailed microscopic analysis of solute diffusion within the SC, we conclude that passive transdermal permeation is affected to only a modest degree (within a factor of ∼2) by the value of D‖lipover the full range of values typically encountered. This statement applies to all but highly lipophilic solutes, i.e., to solutes with log10Koct/w≲5. The transverse diffusivity D⊥lipis a much more quantitatively influential parameter affecting macroscopically observable diffusion in the transdermal direction. Consequently, D⊥lipis the diffusivity that should be used in nondimensionalizing SC diffusion models to reduce computational burden. Furthermore, the analysis lends additional support to previous findings from several groups that transcellular diffusion is the dominant mechanism for passive transdermal permeation for all but the most lipophilic and the most hydrophilic solutes.