Caron Alexis, Lelong Christine, Bartels T, Dorchies O, Gury T, Chalier Catherine, Benning Véronique
Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
Sanofi-Aventis Recherche & Développement, Disposition, Safety & Animal Research, Paris, France.
Regul Toxicol Pharmacol. 2015 Aug;72(3):429-39. doi: 10.1016/j.yrtph.2015.05.022. Epub 2015 May 29.
As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 × 200 μL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome.
8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 × 50, 100 or 200 μL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling.
In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate.
Serial blood sampling (up to 6 × 200 μL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats.
在啮齿动物毒理学研究中，通常会使用卫星动物进行毒代动力学测定，因为连续采血可能会对毒理学终点产生潜在影响。除了毒理学和毒代动力学测定外，从同一动物纵向采集的血样还可用于评估其他参数（如代谢、药效学、安全生物标志物），以最大限度地从啮齿动物中获取可推断的信息。我们研究了在24小时内采集多达6×200μL血液是否可应用于GLP大鼠毒理学研究而不影响科学结果。
8周龄雌性大鼠（200-300g）用标准赋形剂给药长达1个月，并接受或不接受（对照组）连续采血以进行假毒代动力学/辅助测定，使用小型化方法在24小时内采集6×50、100或200μL血液。在采样完成后的几个时间点评估活体终点、临床病理学参数以及对血容量减少敏感的器官的组织病理学。
在采样大鼠中，红细胞量的最小且可逆变化（最大15%）以及肝酶、纤维蛋白原和中性粒细胞的细微变化与任何器官/组织的宏观或微观变化均无关联。
连续采血（24小时内多达6×200μL）与成年大鼠标准毒性终点的评估兼容。
