Department of Physics, Freie Universität Berlin, 14195 Berlin, Germany.
Physical Chemistry, Freie Universität Berlin, 14195 Berlin, Germany.
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3631-3636. doi: 10.1073/pnas.1620636114. Epub 2017 Mar 20.
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.
基于在人体皮肤中抗炎药物地塞米松的实验浓度深度分布，我们通过考虑扩散率和自由能空间变化的 1D 广义扩散方程来模拟随时间变化的药物渗透。为此，我们通过数值反演扩散方程，从而获得药物扩散率和自由能分布作为皮肤深度的函数，而无需进一步的模型假设。作为唯一的输入，使用 X 射线显微镜在三个连续时间点获得的药物浓度分布。对于地塞米松，皮肤屏障功能依赖于在角质层（最外层表皮）中药物扩散率的显著降低的组合，这在短时间内占主导地位，以及在从表皮到下面真皮的过渡处明显的自由能屏障，这决定了药物在长时间内的分布。我们的建模方法通常适用于所有类型的屏障和扩散器，使我们能够将扩散率与自由能效应区分开来。由此，我们可以预测短时间内的药物渗透，在这种情况下实验测量是不可行的，以及长时间的渗透，在这种情况下，离体样本会恶化，从而跨越生物屏障功能的整个时间尺度。
