title: Suitability of skin integrity tests for dermal absorption studies in vitro.
abstract: Skin absorption testing in vitro is a regulatory accepted alternative method (OECD Guideline 428). Different tests can be applied to evaluate the integrity of the skin samples. Here, we compared the pre- or post-run integrity tests (transepidermal electrical resistance, TEER; transepidermal water loss, TEWL; absorption of the reference compounds water, TWF, or methylene blue, BLUE) and additionally focused on co-absorption of a (3)H-labeled internal reference standard (ISTD) as integrity parameter. The results were correlated to absorption profiles of various test compounds. Limit values of 2kΩ, 10 gm(-2)h(-1) and 4.5∗10(-3)cmh(-1) for the standard methods TEER, TEWL and TWF, respectively, allowed distinguishing between impaired and intact human skin samples in general. Single skin samples did, however, not, poorly and even inversely correlate with the test-compound absorption. In contrast, results with ISTD (e.g. (3)H-testosterone) were highly correlated to the absorption of (14)C-labeled test compounds. Importantly, ISTD did not influence analytics or absorption of test compounds. Therefore, ISTD, especially when adjusted to the physico-chemical properties of test compounds, is a promising concept to assess the integrity of skin samples during the whole course of absorption experiments. However, a historical control dataset is yet necessary for a potential routine application.
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany. Electronic address: katharina.guth@basf.com.
authors.forename: Katharina
authors.initials: K
authors.lastname: Guth
authors.affiliation: Freie Universität Berlin, Institute for Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. Electronic address: Monika.Schaefer-Korting@fu-berlin.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany. Electronic address: eric.fabian@basf.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Fabian
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany. Electronic address: robert.landsiedel@basf.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Landsiedel
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: Ben
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000818:Animals; D005260:Female; D005712:Galvanic Skin Response / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000493:pharmacokinetics; D051381:Rats; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D014870:Water Loss, Insensible / Q000187:drug effects
chemical_list: D008751:Methylene Blue
keywords: Dermal absorption; Integrity tests; Internal reference standard; Skin barrier function; TEER; TEWL