Tanaka Yoichi, Takahashi Kazuaki, Hattori Norimichi, Yokoyama Hideaki, Yamaguchi Koki, Shibui Yusuke, Kawaguchi Sayaka, Shimazaki Taishi, Nakai Keiko, Kusuhara Hiroyuki, Saito Yoshiro
Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-ku, Kasasaki-shi, Kanagawa, Japan.
LSIM Safety Institute Corporation., 14-1 Sunayama, Kamisu-shi, Ibaraki, Japan.
Toxicol Rep. 2023 Mar 1;10:334-340. doi: 10.1016/j.toxrep.2023.02.016. eCollection 2023.
According to the ICH S3A Q&A, microsampling is applicable to pharmaceutical drugs and toxicological analysis. Few studies have reported the effect of microsampling on the toxicity of immunotoxicological drugs. The aim of this multicenter study was to evaluate the toxicological effects of serial microsampling on rats treated with azathioprine as a model drug with immunotoxic effects. Fifty microliters of blood were collected from the jugular vein of Sprague-Dawley rats at six time points from day 1 to 2 and 7 time points from day 27 to 28. The study was performed at three organizations independently. The microsampling effect on clinical signs, body weights, food consumption, hematological parameters, biochemical parameters, urinary parameters, organ weights, and tissue pathology was evaluated. Azathioprine-induced changes were observed in certain hematological and biochemical parameters and thymus weight and pathology. Microsampling produced minimal or no effects on almost all parameters; however, at 2 organizations, azathioprine-induced changes were apparently masked for two leukocytic, one coagulation, and two biochemical parameters. In conclusion, azathioprine toxicity could be assessed appropriately as overall profiles even with blood microsampling. However, microsampling may influence azathioprine-induced changes in certain parameters, especially leukocytic parameters, and its usage should be carefully considered.
根据国际人用药品注册技术协调会（ICH）S3A问答文件，微量采样适用于药物和毒理学分析。很少有研究报道微量采样对免疫毒性药物毒性的影响。这项多中心研究的目的是评估连续微量采样对用具有免疫毒性作用的硫唑嘌呤治疗的大鼠的毒理学影响。从第1天到第2天的6个时间点以及从第27天到第28天的7个时间点，从斯普拉格-道利大鼠的颈静脉采集50微升血液。该研究在三个机构独立进行。评估了微量采样对临床体征、体重、食物摄入量、血液学参数、生化参数、尿液参数、器官重量和组织病理学的影响。在某些血液学和生化参数以及胸腺重量和病理学方面观察到了硫唑嘌呤引起的变化。微量采样对几乎所有参数产生的影响极小或没有影响；然而，在两个机构中，硫唑嘌呤引起的两个白细胞参数、一个凝血参数和两个生化参数的变化明显被掩盖。总之，即使采用血液微量采样，也可以将硫唑嘌呤毒性作为整体概况进行适当评估。然而，微量采样可能会影响硫唑嘌呤引起的某些参数变化，尤其是白细胞参数，其使用应谨慎考虑。
