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Regul Toxicol Pharmacol. 2014 Feb;68(1):70-5. doi: 10.1016/j.yrtph.2013.11.007. Epub 2013 Nov 21.

Standardized UV-vis spectra as the foundation for a threshold-based, integrated photosafety evaluation.

Author information

1
Novartis Institutes of BioMedical Research, Preclinical Safety, WKL-136.1.16, 4002 Basel, Switzerland. Electronic address: daniel_manfred.bauer@novartis.com.
2
GSK, GlaxoSmithKline, Platform Technology and Sciences, King of Prussia, PA 19406, USA.
3
Janssen Research and Development, Beerse, Belgium.
4
GSK, GlaxoSmithKline, Projects Clinical Platform and Sciences, King of Prussia, PA 19406, USA.
5
Hoffmann-La Roche, Non-Clinical Drug Safety, 4070 Basel, Switzerland.
6
Pfizer, Global Research and Development, Groton, CT 06340, USA.
7
Sanofi R&D, Montpellier, France.

Abstract

Phototoxicity is a relatively common phenomenon and is an adverse effect of some systemic drugs. The fundamental initial step of photochemical reactivity is absorption of a photon; however, little guidance has been provided thus far regarding how ultraviolet-visible (UV-vis) light absorption spectra may be used to inform testing strategies for investigational drugs. Here we report the results of an inter-laboratory study comparing the data from harmonized UV-vis light absorption spectra obtained in methanol with data from the in vitro 3T3 Neutral Red Uptake Phototoxicity Test. Six pharmaceutical companies submitted data according to predefined quality criteria for 76 compounds covering a wide range of chemical classes showing a diverse but "positive"-enhanced distribution of photo irritation factors (22%: PIF<2, 12%: PIF 2-5, 66%: PIF>5). For compounds being formally positive (PIF value above 5) the lowest reported molar extinction coefficient (MEC) was 1700 L mol⁻¹ cm⁻¹ in methanol. However, the majority of these formally positive compounds showed MEC values being significantly higher (up to almost 40,000 L mol⁻¹ cm⁻¹). In conclusion, an MEC value of 1000 L mol⁻¹ cm⁻¹ may represent a reasonable and pragmatic threshold warranting further experimental photosafety evaluation.

KEYWORDS:

Irradiation; Molar absorptivity; Molar extinction coefficient; Photoreactivity; Photosafety; Phototoxicity; Sunlight; Threshold

PMID:
24269723
DOI:
10.1016/j.yrtph.2013.11.007
[Indexed for MEDLINE]
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