Integrated preclinical photosafety testing strategy for systemically applied pharmaceuticals.
Toxicol Sci
; 139(1): 245-56, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24519524
ABSTRACT
Phototoxic properties of systemically applied pharmaceuticals may be the cause of serious adverse drug reactions. Therefore, a reliable preclinical photosafety assessment strategy, combining in vitro and in vivo approaches in a quantitative manner, is important and has not been described so far. Here, we report the establishment of an optimized modified murine local lymph node assay (LLNA), adapted for phototoxicity assessment of systemically applied compounds, as well as the test results for 34 drug candidates in this in vivo photo-LLNA. The drug candidates were selected based on their ability to absorb ultraviolet/visible light and the photo irritation factors (PIFs) determined in the well-established in vitro 3T3 neutral red uptake phototoxicity test. An in vivo phototoxic potential was identified for 13 of these drug candidates. The use of multiple dose levels in the described murine in vivo phototoxicity studies enabled the establishment of no- and/or lowest-observed-adverse-effect levels (NOAELs/LOAELs), also supporting human photosafety assessment. An in vitro-in vivo correlation demonstrated that a drug candidate classified as "phototoxic" in vitro is not necessarily phototoxic in vivo. However, the probability for a drug candidate to cause phototoxicity in vivo clearly correlated with the magnitude of the phototoxicity identified in vitro.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dermatite Fototóxica
/
Testes de Toxicidade
/
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Toxicol Sci
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
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