{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:31:44Z","timestamp":1777717904540,"version":"3.51.4"},"reference-count":36,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T00:00:00Z","timestamp":1528848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:p>Drug-induced phototoxicity occurs when drugs absorb natural sunlight, leading to chemical reactions causing cellular damage. Distribution to light-exposed tissues is critical and is enhanced by binding to melanin. The International Council on Harmonization S10 guidance document on photosafety evaluation of pharmaceuticals states that although nonpigmented skin tends to be more sensitive than pigmented skin, pigmented skin models should be considered for drugs that bind significantly to melanin. In this study, an in vitro melanin-binding assay was evaluated as prescreening tool for animal model selection. Binding of various structurally diverse phototoxic drugs to synthetic melanin was investigated in vitro and the high-affinity binder sparfloxacin (SPX), moderate-affinity binder 8-methoxypsoralen (8-MOP), and low-affinity binder pirfenidone (PIF) were selected for in vivo studies. Pigmented Brown Norway (BN) rats were compared with nonpigmented Wistar Albino rats to evaluate their sensitivity for the assessment of phototoxicity and skin concentrations of the drugs were measured. For SPX, the onset of phototoxic symptoms was faster for BN rats and drug concentrations were significantly higher in skin of BN rats. For 8-MOP, both models showed comparable sensitivity and skin concentrations did not differ. For the low-affinity binder PIF, no phototoxic effects were observed and skin concentrations in both models were similar. A combined in vitro\/in vivo approach was developed that can be applied for accurate photosafety evaluation of pharmaceuticals based on the assessment of possible melanin-binding effects. In view of the presented data, the pigmented model could be considered for compounds showing a high-affinity binding capacity in vitro.<\/jats:p>","DOI":"10.1177\/1091581818777998","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T21:15:18Z","timestamp":1528924518000},"page":"296-307","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of a Phototoxicity Testing Strategy for Accurate Photosafety Evaluation of Pharmaceuticals Based on the Assessment of Possible Melanin-Binding Effects"],"prefix":"10.1177","volume":"37","author":[{"given":"Jelle","family":"Reinen","sequence":"first","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter","family":"van Sas","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ton","family":"van Huygevoort","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leticia","family":"Rubio","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Scase","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mira","family":"Wenker","sequence":"additional","affiliation":[{"name":"Charles River Laboratories Den Bosch B.V., DD \u2018s-Hertogenbosch, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2018,6,13]]},"reference":[{"key":"bibr1-1091581818777998","doi-asserted-by":"publisher","DOI":"10.5487\/TR.2015.31.2.097"},{"key":"bibr2-1091581818777998","author":"Khandpur S","year":"2016","journal-title":"Br J Dermatol"},{"key":"bibr3-1091581818777998","doi-asserted-by":"crossref","unstructured":"Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol. 1995;33(4):551\u2013736. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/7673488. Accessed August 30, 2016.","DOI":"10.1016\/0190-9622(95)91271-1"},{"key":"bibr4-1091581818777998","doi-asserted-by":"crossref","unstructured":"Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early in vitro identification of phototoxic potential of new drug entities in drug discovery and development. Curr Drug Saf. 2009;4(2):123\u2013136. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19442106. Accessed August 31, 2016.","DOI":"10.2174\/157488609788173044"},{"key":"bibr5-1091581818777998","doi-asserted-by":"crossref","unstructured":"Seto Y, Hosoi K, Takagi H, Exploratory and regulatory assessments on photosafety of new drug entities. Curr Drug Saf. 2012;7(2):140\u2013148. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22873498. 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