Yonezawa Yutaka, Miyashita Taishi, Ashizawa Hiroko, Hashimoto Kazuto, Nejishima Hiroaki, Ogawa Haruko
Pharmacokinetics and Safety Department Drug Research Center Kaken Pharmaceutical Co., Ltd.
J Toxicol Sci. 2017;42(2):145-157. doi: 10.2131/jts.42.145.
Previously, we showed that phototoxicity assessments in Sprague-Dawley (SD) rats can detect phototoxic potential to the same degree as those in guinea pigs. In this study, we examined whether phototoxicity assessments can be incorporated into general toxicology studies, using SD rats. Three phototoxic compounds were tested. Acridine and 8-methoxypsoralen (8-MOP) were transdermally administered, and 8-MOP and lomefloxacin were orally administered. The animals were allocated to three groups for each compound: single-dose, repeated-dose, and repeated-dose plus toxicokinetics (TK). The single-dose group was irradiated with UV-A and UV-B after a single administration of the drug. The repeated-dose and TK groups were irradiated after 8 days of repeated administration of the drug. Blood samples were also collected from the TK group on days 1 and 7 after administration. The phototoxic compounds resulted in skin reactions in all the groups, with no difference in the degree of skin reaction among the three groups. In the TK measurements, all of the phototoxic compounds were detected in the plasma samples, and the irradiation timing was close to the T. These results indicate that phototoxic potential could be evaluated in the TK group, and phototoxicity assessments could be incorporated into general toxicology studies. This reduces the number of studies and animals required, thus shortening the research and development period, and supporting the 3Rs principle of animal experiments. The study also provides information regarding appropriate irradiation timings, differences between the sexes, and dose-response, in turn enabling the phototoxic risk of the compounds to be clearly evaluated.
此前，我们发现对Sprague-Dawley（SD）大鼠进行的光毒性评估与对豚鼠进行的评估一样，能够检测到相同程度的光毒性潜力。在本研究中，我们使用SD大鼠检验了光毒性评估是否可以纳入一般毒理学研究。测试了三种光毒性化合物。吖啶和8-甲氧基补骨脂素（8-MOP）采用经皮给药，8-MOP和洛美沙星采用口服给药。每种化合物的动物被分为三组：单剂量组、重复剂量组和重复剂量加毒代动力学（TK）组。单剂量组在单次给药药物后接受UV-A和UV-B照射。重复剂量组和TK组在药物重复给药8天后接受照射。还在给药后第1天和第7天从TK组采集血样。光毒性化合物在所有组中均导致皮肤反应，三组之间皮肤反应程度无差异。在TK测量中，所有光毒性化合物均在血浆样本中被检测到，且照射时间接近T。这些结果表明，在TK组中可以评估光毒性潜力，并且光毒性评估可以纳入一般毒理学研究。这减少了所需的研究和动物数量，从而缩短了研发周期，并支持动物实验的3R原则。该研究还提供了有关适当照射时间、性别差异和剂量反应方面的信息，进而能够明确评估化合物的光毒性风险。
