Lee Jinsoo, Jeong Ji-Seong, Kim Woojin, Kim Sang Yun, Lee Seung-Jin, Baek Sang-Ki, Lee Jae-Hwan, Jeong Eun Ju, Nam Sang-Yoon, Yu Wook-Joon
Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Daejeon, Republic of Korea; College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Daejeon, Republic of Korea.
Regul Toxicol Pharmacol. 2021 Jul;123:104930. doi: 10.1016/j.yrtph.2021.104930. Epub 2021 Apr 20.
Serial blood sampling for toxicokinetics is generally conducted in regulatory embryo-fetal development (EFD) studies in rats. EFD studies are designed to detect the potential adverse effects of pharmaceuticals on pregnant females and their fetuses; this information is useful for understanding the relationships between systemic exposure levels and toxicity profiles. However, additional satellite pregnant females are needed for toxicokinetics because comprehensive information regarding the potential impact of serial blood sampling on pregnant females is scarce. Here, in this study, we investigated the potential impact of serial blood sampling in pregnant female rats using a typical EFD study design. Additionally, we investigated the additional endpoints (clinical pathology, organ weights, and histopathology) that were deemed likely to be sensitive to blood sampling. Results indicated that serial blood sampling in pregnant females induced physiological adaptive changes and did not affect the general endpoints in EFD studies. Nevertheless, inclusion of satellite groups in EFD studies may be a more prudent approach considering the physiological changes in pregnant females and potential off-target effects of candidate pharmaceuticals. These results provide background information on the impact of serial blood sampling in pregnant females and will be useful to design the regulatory EFD studies.
在大鼠的监管胚胎-胎儿发育（EFD）研究中，通常会进行连续血液采样以获取毒代动力学数据。EFD研究旨在检测药物对怀孕雌性动物及其胎儿的潜在不良影响；这些信息有助于理解全身暴露水平与毒性特征之间的关系。然而，由于关于连续血液采样对怀孕雌性动物潜在影响的全面信息匮乏，毒代动力学研究需要额外的卫星怀孕雌性动物。在此项研究中，我们采用典型的EFD研究设计，调查了连续血液采样对怀孕雌性大鼠的潜在影响。此外，我们还研究了被认为可能对血液采样敏感的其他终点指标（临床病理学、器官重量和组织病理学）。结果表明，怀孕雌性动物的连续血液采样会引起生理适应性变化，但不会影响EFD研究中的一般终点指标。尽管如此，考虑到怀孕雌性动物的生理变化以及候选药物可能的脱靶效应，在EFD研究中纳入卫星组可能是一种更谨慎的方法。这些结果提供了关于连续血液采样对怀孕雌性动物影响的背景信息，将有助于设计监管EFD研究。
