In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study

Sandt, J.J.M. van de; Burgsteden, Johan A. van; Cage, S.; Carmichael, Paul L.; Dick, Ian P; Kenyon, Susan H.; Korinth, Gintautas; Larese, F; Limasset, J. C.; Maas, Wilfred; Montomoli, L; Nielsen, Jesper Bo; Payan, Jean-Paul; Robinson, Edwin H.; Sartorelli, Pietro; Schaller, K. H.; Wilkinson, Simon C.; Williams, Faith M.

doi:10.1016/j.yrtph.2004.02.004

Cited by 195 publications

(121 citation statements)

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“…The use of split skin in in vitro permeation studies is challenging, because skin samples with a constant thickness are difficult to prepare using a dermatome. 20,24) Therefore, few reports have examined the influence of skin thickness on the permeabilities of drugs with different physicochemical properties in in vitro permeation studies using split or stratum corneum-stripped and dermis-split (stripped/split) rat or YMP skin. Nevertheless, we attempted to dermatome the skin using an electric dermatome by a new method established in our previous studies.…”

mentioning

confidence: 99%

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

Takeuchi

Ishida

Furuya

et al. 2012

Biological & Pharmaceutical Bulletin

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The purpose of this study was to clarify the influence of skin thickness on the in vitro permeabilities of 3 model drugs with different physicochemical properties (nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP)) through Sprague-Dawley rat (rat) or Yucatan micropig (YMP) skin. Intact, dermis-split, stratum corneum-stripped or stratum corneum-stripped and dermis-split rat or YMP skin (rat skin thickness: approximately 0.4, 0.9 or 1.2 mm; YMP skin thickness: approximately 0.4, 0.9, 1.8 or 2.8 mm) were set in Franz-type diffusion cells to determine the permeation rate, lag time and resistance ratio of the viable epidermis and dermis against whole skin (R ved /R tot ) of the drugs. The YMP skin permeabilities of the drugs decreased with an increase in the skin thickness, and significant differences were observed in the permeation rates and lag times between intact and dermis-split (0.4 mm) YMP skins. The decreases in the permeabilities of the drugs through the YMP skin were larger than those through the rat skin. The influence of resistances of ISDN and FP through the dermis-split rat or YMP skin was greater at 0.9 mm skin thickness than 0.4 mm skin thickness. The R ved /R tot values for the YMP skins were relatively large for lipophilic drugs (ISDN and FP), and these ratios increased with an increase in the dermis thickness. These results suggest that in vitro skin permeation studies must be done using dermis-split (0.4 mm) skin with the thinnest dermis for predicting in vivo human percutaneous absorption rate.Key words Yucatan micropig; intact skin; stripped skin; split skin; skin permeabilityIn vitro skin permeation studies have been broadly used in the development of transdermal formulations. Animal skins are frequently used as an alternative to human skin in percutaneous absorption studies, because human skin is not always available and the use of human tissues and organs creates ethical problems.1-10) Numerous animal models, including primate, porcine, mouse, rat, guinea pig and pig, have been utilized for skin permeability studies. 1,3,4,[11][12][13] Animal skins with minimal variations in skin permeability may be much better than human skin for determining or estimating the skin permeabilities of drugs and for developing transdermal formulations. 1,14,15) In our previous studies, the in vitro permeation of 3 model drugs was investigated through Sprague-Dawley rat (rat), Yucatan micropig (YMP) and human skin. 16,17) The 3 model drugs were selected because of their different log K o/w values (the logarithm of the octanol/water partition coefficient at 37°C; Table 1). 18) Nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP) were used as hydrophilic, lipophilic and highly lipophilic drugs, respectively. The inter-individual variations in rat and YMP skin permeabilities for the 3 drugs were smaller than the human skin permeability. 16,17) In addition, in vitro permeation studies using rat and YMP skin were particularly useful for evaluating differences in the skin permeabilities o...

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confidence: 99%

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

Takeuchi

Ishida

Furuya

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Critical variables are mainly the inter-individual differences in skin permeability and the source of the skin (e.g., sex, age of donor, body site, skin thickness). 113 Moreover, there are a number of legal and ethical issues. ) deteriorate quickly ex vivo even in fresh specimens.…”

Section: In Vitro Models For Skin Metabolismmentioning

confidence: 99%

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

DumontCoralie

PrietoPilar

AsturiolDavid

et al. 2015

Applied In Vitro Toxicology

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The exposure of the skin to consumer products, drugs, and environmental chemicals can result in their penetrating the skin barrier and entering systemic circulation, potentially resulting in adverse effects in the skin and other organs. The assessment of dermal penetration and bioavailability (including penetration, metabolism, and entry into the systemic circulation) is therefore an important consideration in the risk assessment of chemicals. The skin is a heterogeneous organ with a multilayer structure. Based on its architecture and physiology, substances can penetrate through three major ways but can also be blocked in the different skin layers and in the skin appendages, which act as reservoir. In addition to that, as the skin is a metabolically competent organ, substances can undergo metabolism. After a brief description of the skin architecture, this review will focus on the skin penetration mechanisms and skin metabolic capacities. The skin absorption has traditionally been tested in vivo on animals. However, with the new legislation (i.e., Registration, Evaluation, Authorisation, and Restriction of Chemicals Regulation or Cosmetics Regulation), alternatives to animal testing have to be implemented. In a second part, this review will provide a description of the main in vitro and in silico or computational models available to study skin absorption and skin metabolism (i.e., ex vivo skin models, artificial membrane barriers, primary cells and cell lines, Quantitative Structure-Activity Relationship [QSAR], simulators for the prediction of skin metabolism).

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“…3), and it is used for the same purposes as the static model. Both static and flow-through diffusion cells will work with full thickness as well as epidermal skin barriers [10,11]. Various guidelines indicate that the skin samples that may be used during in vitro studies are split thickness [6] or when justified, full thickness up to 1 mm.…”

Section: Skin Penetration Models For In Vitro Studiesmentioning

confidence: 99%

Percutaneous Penetration ‐ Methodological Considerations

Holmgaard

Benfeldt

Nielsen

2014

Basic Clin Pharma Tox

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Studies on percutaneous penetration are needed to assess the hazards after unintended occupational skin exposures to industrial products as well as the efficacy after intended consumer exposure to topically applied medicinal or cosmetic products. During recent decades, a number of methods have been developed to replace methods involving experimental animals. The results obtained from these methods are decided not only by the chemical or product tested, but to a significant degree also by the experimental set-up and decisions made by the investigator during the planning phase. The present MiniReview discusses some of the existing and well-known experimental in vitro and in vivo methods for studies of percutaneous penetration together with some more recent and promising methods. After this, some considerations and recommendations about advantages and limitations of the different methods and their relevance for the prediction of percutaneous penetration are given. Which method to prefer will depend on the product to be tested and the question asked. Regulatory guidelines exist for studies on percutaneous penetration, but researchers as well as regulatory bodies need to pay specific attention to the vehicles and solvents used in donor and sampling fluids so that it reflects in-use conditions as closely as possible. Based on available experimental data, mathematical models have been developed to aid predictions of skin penetration. The authors question the general use of the present mathematical models in hazard assessment, as they seem to ignore outliers among chemicals as well as the heterogeneity of skin barrier properties and skin conditions within the exposed populations. This MiniReview will discuss some of the existing and wellknown experimental in vitro and in vivo models together with some more recent and promising models and give some considerations and recommendations about advantages and limitations of the various models and their relevance for predictions of percutaneous penetration. An overview of the methodologies discussed can be found in table 1.Dermal exposure may be unintentional after environmental or occupational exposure or intentional after the use of topically applied medication or use of cosmetic products. In all cases, the assessment of the potential for percutaneous penetration or temporary deposition within the skin is an essential element in assessing risk as well as efficacy after dermal exposures.Decades of preventive efforts have decreased the inhalational exposures at work places. At the same time, topically applied pharmaceuticals are being used ever more often. Together, this has increased the relative importance of dermal exposures.Knowledge concerning percutaneous penetration and the potential to reach target sites closes the gap from exposure assessment and hazard identification to risk assessment. If a substance is unable to penetrate the stratum corneum (SC) or affect the skin barrier function in any way, then the need for further assessment of risk becomes less evide...

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In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study

Cited by 195 publications

References 11 publications

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

Influence of Skin Thickness on the in Vitro Permeabilities of Drugs through Sprague-Dawley Rat or Yucatan Micropig Skin

Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

Percutaneous Penetration ‐ Methodological Considerations

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