Nonclinical toxicology studies with sodium taurodeoxycholate: acute and subacute toxicity in dogs

Sodium taurodeoxycholate (TDCA) has been investigated for various inflammatory disorders such as sepsis. We recently evaluated nonclinical safety profile of TDCA using rats infused intravenously. As a series of preclinical safety investigations, we further conducted toxicity studies with TDCA delivered to dogs via intravenous administration under Good Laboratory Practice regulation in this study. In dose range-finding study (dose escalation study), dogs given with TDCA at a dose of 150 mg/kg showed marked changes in clinical signs, hematology, and serum biochemistry. And biochemical markers of liver damage and local skin lesions were observed following intravenous infusion of 100 mg/kg TDCA, suggesting that 100 mg/kg was chosen as the highest dose of TDCA for 4-week repeated-dose toxicity study using dogs. Despite no treatment-related significant changes in body weight, food consumption, ophthalmoscopy, and urinalysis, skin lesions were observed at the injection site of animals administered with higher than 50 mg/kg of TDCA along with biochemical and histopathological changes associated with liver injury. However, most of off-target effects were found to be reversible since these were recovered after stopping TDCA infusion. These findings indicate that the no-observed-adverse-effect-level (NOAEL) for TDCA in dogs was considered to be 5 mg/kg/d. Taken together, our results provide important toxicological profiles regarding the safe dose of TDCA for drug development or clinical application.

牛磺脱氧胆酸钠（Sodium taurodeoxycholate, TDCA）已被研究用于脓毒症等多种炎症性疾病。我们近期通过静脉输注大鼠评估了TDCA的非临床安全性概况。作为一系列临床前安全性研究，本研究中我们进一步依照良好实验室规范（Good Laboratory Practice, GLP），对犬开展静脉给予TDCA的毒性研究。在剂量范围探索试验（剂量递增试验）中，给予150mg/kg TDCA的犬出现了临床体征、血液学指标及血清生化指标的显著异常。在静脉输注100mg/kg TDCA后，研究人员观察到肝损伤生化标志物升高以及局部皮肤病变，因此选择100mg/kg作为犬4周重复给药毒性试验的最高给药剂量。尽管体重、食物消耗量、眼科检查结果与尿液分析均未出现与治疗相关的显著变化，但在给药剂量高于50mg/kg的动物注射部位观察到皮肤病变，同时伴随与肝损伤相关的生化及组织病理学改变。不过，多数非靶标效应均为可逆性，在停止TDCA输注后这些异常均可恢复。上述结果表明，犬体内TDCA的未观察到不良反应水平（no-observed-adverse-effect-level, NOAEL）被确定为5mg/kg/天。综上，本研究结果为TDCA用于药物开发或临床应用的安全剂量提供了重要的毒理学依据。