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。我们此前通过静脉输注给药的大鼠模型，评估了TDCA的非临床安全性特征。作为一系列临床前安全性研究的一部分，本研究遵循良好实验室规范（Good Laboratory Practice, GLP），通过静脉给药途径，对犬开展了TDCA的毒性研究。在剂量范围探索试验（剂量递增试验）中，给药剂量达150mg/kg的犬出现了临床体征、血液学及血清生化指标的显著异常。当以100mg/kg剂量静脉输注TDCA时，可观察到肝损伤生化标志物升高及局部皮肤损伤，因此选定100mg/kg作为犬4周重复给药毒性试验的最高给药剂量。尽管给药未对动物的体重、摄食量、眼科检查结果及尿液分析指标造成与处理相关的显著改变，但当给药剂量高于50mg/kg时，动物注射部位出现皮肤损伤，同时伴随与肝损伤相关的生化及组织病理学变化。不过，绝大多数脱靶效应具有可逆性，在停止TDCA输注后相关异常可恢复。上述结果表明，犬给药TDCA的未观察到不良反应水平（no-observed-adverse-effect-level, NOAEL）为5mg/kg/天。综上，本研究结果为TDCA用于药物研发或临床应用的安全剂量提供了重要的毒理学依据。