Hiroto Ohtake,Yukiko Suzuki,Masashi Kato,Yoshiki Seto, Satomi Onoue

Department of Pharmacokinetics and Pharmacodynamics,School of Pharmaceutical Sciences,University of Shizuoka,52-1Yada,Suruga-ku,Shizuoka 422-8526,Japan

Photosafety testing of dermally-applied chemicals based on photochemical and cassette-dosing pharmacokinetic data

Hiroto Ohtake,Yukiko Suzuki,Masashi Kato,Yoshiki Seto, Satomi Onoue*

Department of Pharmacokinetics and Pharmacodynamics,School of Pharmaceutical Sciences,University of Shizuoka,52-1Yada,Suruga-ku,Shizuoka 422-8526,Japan

A R T I C L E I N F O

Article history:

Available online 25 November 2015

Photosafety assessment

Phototoxicity

Photoreactivity

Pharmacokinetics

Drug-induced phototoxicity is elicited by exposure of skin and/ or eyes to topical or systemic administration of chemicals, followed by exposure to sunlight.For photosafety testing,a new screening strategy,employing in vitro photochemical/ photobiological and in vivo cassette-dosing pharmacokinetic (PK)studies,was proposed[1,2].The screening system provided reliable phototoxic predictions of tested chemicals at least within the same chemical series;however,the applicability of the proposed strategy is not fully understood.The present work aimed to verify the prediction performance for this photosafety screening on dermally-applied chemicals with wide chemical diversity.

Five chemicals,namely 2-acetonaphthalene(AN),4′-methylbenzylidene camphor(MB),6-methylcoumarin(MC), methyl N-methylanthranilate(MM),and sulisobenzone(SB), were selected as model compounds.Their photochemical properties were evaluated by UV/Visible spectral analysis and micellar reactive oxygen species(mROS)assay,and an in vivo dermal cassette-dosing PK test was carried out.An in vivo phototoxicity test in rats was also conducted on each tested chemical for comparison purpose.All tested chemicals exhibited strong UVA/B absorption with molar extinction coeffcients of over 3000 M–1·cm–1.AN,MC and MM exhibited signifcant ROS generation upon exposure to simulated sunlight;however,ROS generation from MB and SB was negligible.According to skin concentration–time profles in rat,the Cmaxvalues of AN and MB were calculated to be ca.10.9 and 12.6 μg/g tissue,and the MRT values of AN and MB were estimated to be ca.39.3 and >11.9 h,respectively,suggesting long-lasting exposure of these chemicals to skin after dermal administration than the other tested chemicals.On the basis of the in vitro photochemical and in vivo PK data obtained,the order of phototoxic potential was deduced as follows:AN>MC>MM>>MB>SB(Table 1). In the in vivo phototoxicity test,AN and MM caused remarkable phototoxic skin responses in rats,and in contrast,in vivo phototoxicity on MB and SB was negligible.The observed in vivophototoxicity of tested chemicals could be rated as follows: AN≒MM>MC>>MB≒SB.The predicted phototoxic risk of tested chemicals based on the proposed screening strategy was almost in agreement with the in vivo phototoxicity.From the present fndings,the proposed photosafety screening would be of use to assess the phototoxic potential of dermallyapplied chemicals with wide chemical diversity.The proposed photosafety testing strategy employing photochemical and cassette-dosing pharmacokinetic data would have high prediction capacity and wide applicability.

Table 1–Decision matrix for phototoxic predictions

R E F E R E N C E S

[1]Onoue S,Kato M,Inoue R,et al.Photosafety screening of phenothiazine derivatives with combined use of photochemical and cassette-dosing pharmacokinetic data. Toxicol Sci 2013;137(2):469–477.

[2]Seto Y,Ohtake H,Kato M,et al.Phototoxic risk assessments on benzophenone derivatives:photobiochemical assessments and dermal cassette-dosing pharmacokinetic study.J Pharmacol Exp Ther 2015;354:195–202.

*E-mail address:onoue@u-shizuoka-ken.ac.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.11.014

1818-0876/?2016 Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).