Finite dose skin mass balance including the lateral part: comparison between experiment, pharmacokinetic modeling and diffusion models.

This work investigates in vitro finite dose skin absorption of the model compounds flufenamic acid and caffeine experimentally and mathematically. The mass balance in different skin compartments (donor, stratum corneum (SC), deeper skin layers (DSL), lateral skin parts and acceptor) is analyzed as a function of time. For both substances high amounts were found in the lateral skin compartment after 6h of incubation, which emphasizes not to elide these parts in the modeling. Here, three different mathematical models were investigated and tested with the experimental data: a pharmacokinetic model (PK), a detailed microscopic two-dimensional diffusion model (MICRO) and a macroscopic homogenized diffusion model (MACRO). While the PK model was fitted to the experimental data, the MICRO and the MACRO models employed input parameters derived from infinite dose studies to predict the underlying diffusion process. All models could satisfyingly predict or describe the experimental data. The PK model and MACRO model also feature the lateral parts.

Nonlinear anisotropic diffusion filtering of three-dimensional image data from two-photon microscopy.

Two-photon microscopy in combination with novel fluorescent labeling techniques enables imaging of three-dimensional neuronal morphologies in intact brain tissue. In principle it is now possible to automatically reconstruct the dendritic branching patterns of neurons from 3-D fluorescence image stacks. In practice however, the signal-to-noise ratio can be low, in particular in the case of thin dendrites or axons imaged relatively deep in the tissue. Here we present a nonlinear anisotropic diffusion filter that enhances the signal-to-noise ratio while preserving the original dimensions of the structural elements. The key idea is to use structural information in the raw data-the local moments of inertia-to locally control the strength and direction of diffusion filtering. A cylindrical dendrite, for example, is effectively smoothed only parallel to its longitudinal axis, not perpendicular to it. This is demonstrated for artificial data as well as for in vivo two-photon microscopic data from pyramidal neurons of rat neocortex. In both cases noise is averaged out along the dendrites, leading to bridging of apparent gaps, while dendritic diameters are not affected. The filter is a valuable general tool for smoothing cellular processes and is well suited for preparing data for subsequent image segmentation and neuron reconstruction.

Non steady-state descriptions of drug permeation through stratum corneum. I. The biphasic brick-and-mortar model.

PURPOSE: The diffusion equation should be solved for the non-steady-state problem of drug diffusion within a two-dimensional, biphasic stratum corneum membrane having homogeneous lipid and corneocyte phases. METHODS: A numerical method was developed for a brick-and-mortar SC-geometry, enabling an explicit solution for time-dependent drug concentration within both phases. The lag time and permeability were calculated. RESULTS: It is shown how the barrier property of this model membrane depends on relative phase permeability, corneocyte alignment, and corneocyte-lipid partition coefficient. Additionally, the time-dependent drug concentration profiles within the membrane can be observed during the lag and steady-state phases. CONCLUSIONS: The model SC-membrane predicts, from purely morphological principles, lag times and permeabilities that are in good agreement with experimental values. The long lag times and very small permeabilities reported for human SC can only be predicted for a highly-staggered corneocyte geometry and corneocytes that are 1000 times less permeable than the lipid phase. Although the former conclusion is reasonable, the latter is questionable. The elongated, flattened corneocyte shape renders lag time and permeability insensitive to large changes in their alignment within the SC. Corneocyte/lipid partitioning is found to be fundamentally different to SC/donor partitioning, since increasing drug lipophilicity always reduces both lag time and permeability.