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

Version 2 2021-01-05, 07:20
Version 1 2019-06-19, 11:32
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posted on 2021-01-05, 07:20 authored by Hyung Jun Choi, Jun-Won Yun, Youn-Hee Kim, Euna Kwon, Min-Kyong Hyon, Ji Young Kim, Jeong-Hwan Che, Jin-Sung Park, Hyoung-Chin Kim, Woo Ho Kim, Seung-Yong Seong, Byeong-Cheol Kang

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.

Funding

This work was supported by a grant funded by the National Research Foundation, Ministry of Science, ICT and future planning (2012R1A5A2A44671346) and a grant from the Korea Healthcare Technology R&D Project, Ministryof Health and Welfare (A062260), Republic of Korea.

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