Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice

Kim,Seong‑Kwan; Shin,Soo‑Jeong; Yoo,Yohan; Kim,Na‑Hyun; Kim,Dong‑Soon; Zhang,Dan; Park,Jin‑A; Yi,Hee; Kim,Jin‑Suk; Shin,Ho‑Chul

doi:10.3892/etm.2015.2203

Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice

Authors:
- Seong‑Kwan Kim
- Soo‑Jeong Shin
- Yohan Yoo
- Na‑Hyun Kim
- Dong‑Soon Kim
- Dan Zhang
- Jin‑A Park
- Hee Yi
- Jin‑Suk Kim
- Ho‑Chul Shin
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Affiliations: Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143‑701, Republic of Korea, Jayang High School, Seoul 143‑861, Republic of Korea, Konkuk University High School, Seoul 143‑701, Republic of Korea
Published online on: January 22, 2015 https://doi.org/10.3892/etm.2015.2203
Pages: 853-859

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Abstract

An oral toxicity study of several pregnancy category X drugs was performed in female ICR mice. The drugs were administered orally once daily for 3 days at doses of 1, 10 and 100 µg/kg for isotretinoin; 6.7, 67 and 670 µg/kg for misoprostol; 83, 830 and 8,300 µg/kg for methotrexate; 3.3, 33 and 330 µg/kg for mifepristone; and 25, 250 and 2,500 µg/kg for levonorgestrel. During the test period, clinical signs, mortality, body weight, hematology, serum biochemistry and necropsy findings were examined. Following administration of methotrexate at 8,300 µg/kg, a number of animals exhibited decreased spontaneous activity, and one animal died. In the hematological analysis, compared with those treated with the control, the animals treated with the drugs exhibited similar significant decreases in the number of granulocytes and granulocyte differentiation, and increases in lymphocyte differentiation. In the serum biochemical analysis, animals receiving high doses of the five drugs demonstrated significant changes in uric acid, glucose, alkaline phosphatase, total bilirubin, lipase, total cholesterol and calcium. At necropsy, intestinal redness was frequently observed in animals that received the high dose of methotrexate. Uterus enlargement and ovary dropsy were also detected in the groups receiving mifepristone and levonorgestrel. Despite the short‑term exposure, these drugs exhibited significant side effects, including white blood cell toxicity, in the mouse model. Category X drugs can be traded illegally via the internet for the purpose of early pregnancy termination. Thus, illegal abuse of the drugs should be further discouraged to protect mothers.

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