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Drug Chem Toxicol. 2019 Jun 19:1-9. doi: 10.1080/01480545.2019.1566352. [Epub ahead of print]

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

Author information

1
a Graduate School of Translational Medicine , College of Medicine, Seoul National University , Seoul , Republic of Korea.
2
b Department of Experimental Animal Research , Biomedical Research Institute Seoul National University Hospital , Seoul , Republic of Korea.
3
c Department of Biotechnology , The Catholic University of Korea , Bucheon , Republic of Korea.
4
d Department of Microbiology and Immunology, Department of Biomedical Sciences , Wide River Institute of Immunology, Seoul National University College of Medicine , Seoul , Republic of Korea.
5
e Biomedical Center for Animal Resource and Development , Seoul National University College of Medicine , Seoul , Republic of Korea.
6
f Laboratory Animal Resource Center , Korea Research Institute of Bioscience and Biotechnology , Cheongju , Republic of Korea.
7
g Department of Pathology , Seoul National University College of Medicine , Seoul , Republic of Korea.
8
h Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University , Pyeongchang-gun , Republic of Korea.

Abstract

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.

KEYWORDS:

Taurodeoxycholate; acute toxicity; bile acid; dog; sepsis; subacute toxicity

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