Phototoxic Risk Assessments on Benzophenone Derivatives: Photobiochemical Assessments and Dermal Cassette-Dosing Pharmacokinetic Study
Phototoxic Risk Assessments on Benzophenone Derivatives: Photobiochemical Assessments and Dermal Cassette-Dosing Pharmacokinetic Study
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二苯甲酮衍生物的光毒性风险评估：光生化评估和皮肤盒给药药代动力学研究
DOI：
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发表时间：
2015
影响因子：
3.5
通讯作者：
S. Onoue
中科院分区：
文献类型：
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作者：
Yoshiki Seto;Hiroto Ohtake;Masashi Kato;S. Onoue
本研究旨在根据皮肤化学物质的光化学和药代动力学 (PK) 数据来验证光安全性筛查。选择六种二苯甲酮衍生物（BZPs）作为模型化合物，进行体外光化学/光毒性表征和皮肤盒给药PK研究。为了进行比较，还进行了体内光毒性测试。所有BZP都表现出强烈的UVA/UVB吸收，摩尔消光系数超过2000 M−1 × cm−1，二苯甲酮和酮洛芬在暴露于模拟阳光下时表现出显着的活性氧（ROS）生成（约2.0 mW/cm2）；然而，磺异苯酮和二氧苯酮产生的 ROS 可以忽略不计。为了验证体外光毒性，进行了3T3中性红摄取光毒性试验，将二苯甲酮和酮洛芬归类为光毒性化学品。酮洛芬的皮肤 PK 参数表明所有测试的 BZP 的皮肤分布最高。根据其体外光化学/光毒性和 PK 数据，酮洛芬被推断具有高度光毒性。根据所提出的筛选策略预测的 BZP 光毒性风险排序与体内光毒性测试的结果几乎一致。光化学和盒式给药 PK 数据的结合使用将为具有高生产力的候选者提供光毒性风险的可靠预测。
This study aimed to qualify photosafety screening on the basis of photochemical and pharmacokinetic (PK) data on dermally applied chemicals. Six benzophenone derivatives (BZPs) were selected as model compounds, and in vitro photochemical/phototoxic characterization and dermal cassette-dosing PK study were carried out. For comparison, an in vivo phototoxicity test was also conducted. All of the BZPs exhibited strong UVA/UVB absorption with molar extinction coefficients of over 2000 M−1 × cm−1, and benzophenone and ketoprofen exhibited significant reactive oxygen species (ROS) generation upon exposure to simulated sunlight (about 2.0 mW/cm2); however, ROS generation from sulisobenzone and dioxybenzone was negligible. To verify in vitro phototoxicity, a 3T3 neutral red uptake phototoxicity test was carried out, and benzophenone and ketoprofen were categorized to be phototoxic chemicals. The dermal PK parameters of ketoprofen were indicative of the highest dermal distribution of all BZPs tested. On the basis of its in vitro photochemical/phototoxic and PK data, ketoprofen was deduced to be highly phototoxic. The rank of predicted phototoxic risk of BZPs on the basis of the proposed screening strategy was almost in agreement with the results from the in vivo phototoxicity test. The combined use of photochemical and cassette-dosing PK data would provide reliable predictions of phototoxic risk for candidates with high productivity.