Data-based modeling of drug penetration relates human skin barrier function to the interplay of diffusivity and free-energy profiles

Abstract

Based on experimental concentration depth profiles of the antiinflammatory drug dexamethasone in human skin, we model the time-dependent drug penetration by the 1D general diffusion equation that accounts for spatial variations in the diffusivity and free energy. For this, we numerically invert the diffusion equation and thereby obtain the diffusivity and the free-energy profiles of the drug as a function of skin depth without further model assumptions. As the only input, drug concentration profiles derived from X-ray microscopy at three consecutive times are used. For dexamethasone, skin barrier function is shown to rely on the combination of a substantially reduced drug diffusivity in the stratum corneum (the outermost epidermal layer), dominant at short times, and a pronounced free-energy barrier at the transition from the epidermis to the dermis underneath, which determines the drug distribution in the long-time limit. Our modeling approach, which is generally applicable to all kinds of barriers and diffusors, allows us to disentangle diffusivity from free-energetic effects. Thereby we can predict short-time drug penetration, where experimental measurements are not feasible, as well as long-time permeation, where ex vivo samples deteriorate, and thus span the entire timescales of biological barrier functioning.M ulticellular organisms exhibit numerous structurally distinct protective barriers, such as the blood-brain barrier; intestinal, mouth, and respiratory mucosa; and the skin, the largest human organ. These barriers are generally designed to keep foreign material out and in some cases to allow the highly regulated transfer of certain desired molecules; consequently, they present a severe challenge for drug delivery (1-3). The indepth understanding of barrier function is not only required for controlled drug delivery, but also of central interest in medicine, drug development, and biology.Human skin can be broadly divided into two layers (Fig. 1A): the epidermis with a thickness of about 100 µm, which prevents water loss and the entrance of harmful microorganisms or irritants, and the dermis, which is typically 2 mm thick, contains blood vessels, and protects the body from mechanical stress (4). The epidermis is further divided into the stratum corneum (SC), the 10-to 20-µm thick outermost layer consisting of dried-out dead skin cells, the corneocytes, and the viable epidermis (VE). In the stratum granulosum (SG), which is part of the VE, skin cells (keratinocytes) are gradually flattened and transformed into corneocytes when migrating toward the SC.The SC is structurally similar to a brick wall (5): The bricks are the corneocytes, whereas the mortar is the intercellular matrix, which is composed of stacked lipid bilayers. Several models for the permeation of drugs through skin exist, which incorporate the skin structure on different levels of complexity. In the simplest models the stratified skin structure is reflected by 1D layers with different diffusivities and partition coefficients (6-10), and in ...

Influence of polar co-solutes and salt on the hydration of lipid membranes

“…(B) Same decomposition for DMPC membranes loaded with 10 wt% TMAO. Open squares are theoretical predictions according to eqn (8). (C) Comparison between experiments and simulations of POPC lipids, regarding the change DH 0 in the differential hydration enthalpy H 0 = dH/dn w due to addition of 5 wt% TMAO.…”

“…The best-matching weighting coefficients (K POPC = 2.23 and K DMPC = 2.29), however, significantly deviate from unity. This deviation can be attributed to the following shortcomings of eqn (8). Firstly, the interaction between TMAO molecules in concentrated solutions is a multi-body problem and deviates from the sum of pair-wise interactions.…”

“…Firstly, the interaction between TMAO molecules in concentrated solutions is a multi-body problem and deviates from the sum of pair-wise interactions. And second, eqn (8) neglect interactions between TMAO and the PC headgroups of the lipids. These interactions are likely of similar nature as the TMAO/TMAO interactions, due to the dipolar/hydrophobic architecture of both TMAO and PC, and also comparable in number.…”

“…7 It exhibits very low permeability for hydrophilic and hydrophobic molecules. 8 In nature, protection against osmotic stress is commonly achieved by the release of small polar co-solutes with low vapor pressure, sometimes referred to as osmolytes. 9,10 These molecules serve to retain the physiological, fluid state of membrane systems in low humidity conditions.…”

External Potential Modifies Friction of Molecular Solutes in Water

“…While this is unproblematic for static properties such as free-energy profiles, our results show that this procedure potentially perturbs kinetic properties such as the diffusivity profile. In fact, there are various alternative techniques that allow us to extract free-energy and diffusivity profiles from simulation trajectories of unconstrained solutes [10,11] and which therefore do not suffer from this potential complication.…”