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Toxicity of topically applied drugs beyond skin irritation: Static skin model vs. Two organs-on-a-chip.
Tavares, R S N; Tao, Thi Phuong; Maschmeyer, I; Maria-Engler, S S; Schäfer-Korting, M; Winter, A; Zoschke, C; Lauster, R; Marx, U; Gaspar, L R.
Afiliação
  • Tavares RSN; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Bairro Monte Alegre, Ribeirão Preto, SP, Brazil.
  • Tao TP; TissUse GmbH, Oudenarder Str. 16, 13347 Berlin, Germany.
  • Maschmeyer I; TissUse GmbH, Oudenarder Str. 16, 13347 Berlin, Germany.
  • Maria-Engler SS; Clinical and Toxicological Analyses Department, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP 05508-000, Brazil.
  • Schäfer-Korting M; Institute of Pharmacy (Pharmacology & Toxicology), Freie Universität, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
  • Winter A; TissUse GmbH, Oudenarder Str. 16, 13347 Berlin, Germany.
  • Zoschke C; Institute of Pharmacy (Pharmacology & Toxicology), Freie Universität, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
  • Lauster R; Technische Universität, Institute of Biotechnology, Chair of Medical Biotechnology, Gustav-Meyer-Allee 25, 13355 Berlin, Germany.
  • Marx U; TissUse GmbH, Oudenarder Str. 16, 13347 Berlin, Germany.
  • Gaspar LR; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Bairro Monte Alegre, Ribeirão Preto, SP, Brazil. Electronic address: lorena@fcfrp.usp.br.
Int J Pharm ; 589: 119788, 2020 Nov 15.
Article em En | MEDLINE | ID: mdl-32882369
Skin model cultivation under static conditions limits the observation of the toxicity to this single organ. Biology-inspired microphysiological systems associating skin with a liver in the same circulating medium provide a more comprehensive insight into systemic substance toxicity; however, its advantages or limitations for topical substance toxicity remain unknown. Herein, we performed topical (OECD test guideline no. 439) and systemic administration of terbinafine in reconstructed human skin (RHS) vs. a RHS plus liver model cultured in TissUse' HUMIMIC Chip2 (Chip2). Aiming for a more detailed insight into the cutaneous substance irritancy/toxicity, we assessed more than the MTT cell viability: lactate dehydrogenase (LDH), lactate and glucose levels, as well as inherent gene expressions. Sodium dodecyl sulfate (SDS) was the topical irritant positive control. We confirmed SDS irritancy in both static RHS and Chip2 culture by the damage in the morphology, reduction in the lactate production and lower glucose consumption. In the static RHS, the SDS-treated tissues also released significantly high LDH (82%; p < 0.05) and significantly lower IL-6 release (p < 0.05), corroborating with the other metabolic levels. In both static RHS and Chip2 conditions, we confirmed absence of irritancy or systemic toxicity by LDH, glucose or lactate levels for topical 1% and 5% terbinafine and systemic 0.1% terbinafine treatment. However, topical 5% terbinafine treatment in the Chip2 upregulated IL-1α in the RHS, unbalanced apoptotic and proliferative cell ratios in the liver and significantly increased its expression of CYP1A2 and 3A4 enzymes (p < 0.05), proving that it has passed the RHS barrier promoting a liver impact. Systemic 0.1% terbinafine treatment in the Chip2 increased RHS expression of EGFR, increased apoptotic cells in the liver, downregulated liver albumin expression and upregulated CYP2C9 significantly (p < 0.05), acting as an effective hepatotoxic terbinafine control. The combination of the RHS and liver model in the Chip2 allowed a more sensitive assessment of skin and hepatic effects caused by chemicals able to pass the skin (5% terbinafine and SDS) and after systemic 0.1% terbinafine application. The present study opens up a more complex approach based on the microphysiological system to assess more than a skin irritation process.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas Tipo de estudo: Guideline Limite: Humans Idioma: En Revista: Int J Pharm Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas Tipo de estudo: Guideline Limite: Humans Idioma: En Revista: Int J Pharm Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda