Prediction of Percutaneous Absorption in Human Using Three-Dimensional Human Cultured Epidermis LabCyte EPI-MODEL

Abstract

The objective of this study is to establish a relationship of the skin penetration parameters between the three-dimensional cultured human epidermis LabCyte EPI-MODEL (LabCyte) and hairless mouse (HLM) skin penetration in vitro and to predict the skin penetration and plasma concentration profile in human. The skin penetration experiments through LabCyte and HLM skin were investigated using 19 drugs that have a different molecular weight and lipophilicity. The penetration flux for LabCyte reached 30 times larger at maximum than that for HLM skin. The human data can be estimated from the in silico approach with the diffusion coefficient (D), the partition coefficient (K) and the skin surface concentration (C) of drugs by assuming the bi-layer skin model for both LabCyte and HLM skin. The human skin penetration of β-estradiol, prednisolone, testosterone and ethynylestradiol was well agreed between the simulated profiles and in vitro experimental data. Plasma concentration profiles of β-estradiol in human were also simulated and well agreed with the clinical data. The present alternative method may decrease human or animal skin experiment for in vitro skin penetration.Key words in silico correlation; reconstructed epidermis; LabCyte EPI-MODEL; hairless mouse Human skin permeability of drugs in vivo can be estimated from in vitro experiment using human skin. However, some researchers have ethical and cultural difficulty to get human skins. Thus, animal skins have been widely used for pharmaceutical, toxicological and cosmetic R&D although the skins have a species difference between human. Recently, the 7th Amendment of the EC Cosmetic Directive prohibits the sale of cosmetics and ingredients validated their safety by animal testing with an alternative method. 1) Thus, researchers utilize reconstructed human skin instead of animal skin. The experiments used reconstructed epidermis is approved by the European Centre for the Validation of Alternative Methods (ECVAM) as the scientifically validated methods for skin corrosion and irritation. 2,3) Permeability studies with Episkin ® , EpiDerm TM and SkinEthic ® comparison to human and animal skin were investigated and the authors reported that the penetration flux through the reconstructed skin was higher than that of skin. [4][5][6] The OECD regulations accepted the results from the reconstructed skin 7) but don't approve it as an alternative method for in vitro human skin penetration experiment yet.Skin penetration is widely expressed by the mathematical models on the basis of the process of diffusion and dissolution. Penetration parameters, diffusion coefficient D [cm 2 /s] and partition coefficient K [-], through stratum corneum (SC) and viable skin (VS) of hairless mouse skin are found to well agree with that of human skin. 8) Not only the skin penetration profile but the blood concentration profile in human is well simulated using the penetration parameters determined from hairless mouse skin, the thickness of human SC and VS, the skin enzymatic parameters (first-ord...

Evaluation of a Silicone Membrane as an Alternative to Human Skin for Determining Skin Permeation Parameters of Chemical Compounds

“…That is the reason for the observation of the relationship in DL −2 and KL between silicone membrane and human or animal skin in the present study. Previously, the permeabilities in human skin and hairless rat skin have been shown to correlate with those in alternative membranes, such as a three-dimensional cultured human skin model, [5][6][7] PAMPA, [8][9][10] and Strat-M . 11) On the other hand, silicone membranes have long been available as an alternative membrane in in vitro permeation studies.…”

“…In vitro permeation studies of various model compounds have been conducted using a three-dimensional cultured human skin model, [5][6][7] a parallel artificial membrane permeability assay (PAMPA), [8][9][10] and Strat-M , 11) and these studies have shown the utility of skin surrogates. A study of silicone membrane permeability has been conducted previously, 12) and silicone has been used in various other studies to determine, for example, the effects of vehicles on membrane permeability, 13) prediction of skin concentrations of test compounds, 14) and skin permeation routes.…”

In vitro Analysis of the Effect of Alkyl-Chain Length of Anionic Surfactants on the Skin by Using a Reconstructed Human Epidermal Model

“…While it is has been shown that the stratum corneum structure in the LabCyte EPI-MODEL24 delays the permeation of chemicals 21 , the barrier function of the LabCyte EPI-MODEL24 is weaker than that observed in humans and animals 22 . Surfactants, such as AS and MES, must easily permeate and disturb the protein and lipid domains in the epidermis.…”

Impact of Humidity on In Vitro Human Skin Permeation Experiments for Predicting In Vivo Permeability

“…Some reports were published using SKIN‐CAD ® for prediction of in vivo skin permeability . The predictions were based on the result of in vitro skin permeation experiments using animal skins or three‐dimensional human cultured epidermis.…”

“…Some reports were published using SKIN-CAD R for prediction of in vivo skin permeability. 7,14,[18][19][20] The predictions were based on the result of in vitro skin permeation experiments using animal skins or three-dimensional human cultured epidermis. This study is the first approach predicting human plasma concentration profiles using the result of in vitro human skin permeation experiments and SKIN-CAD R .…”