Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone
OBJECTIVE: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs.
METHODS: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses.
RESULTS: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight.
CONCLUSION: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Toxicology mechanisms and methods - 26(2016), 1 vom: 08., Seite 36-45 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xiao, Yingying [VerfasserIn] |
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| Links: |
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| Themen: |
320T6RNW1F |
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| Anmerkungen: |
Date Completed 14.12.2016 Date Revised 30.12.2016 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.3109/15376516.2015.1118715 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM257770275 |
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| 041 | |a eng | ||
| 100 | 1 | |a Xiao, Yingying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone |
| 264 | 1 | |c 2016 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 14.12.2016 | ||
| 500 | |a Date Revised 30.12.2016 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a OBJECTIVE: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs | ||
| 520 | |a METHODS: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses | ||
| 520 | |a RESULTS: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight | ||
| 520 | |a CONCLUSION: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Acute toxicity | |
| 650 | 4 | |a liver toxicity | |
| 650 | 4 | |a metapristone | |
| 650 | 4 | |a mifepristone | |
| 650 | 4 | |a subacute toxicity | |
| 650 | 7 | |a Abortifacient Agents, Steroidal |2 NLM | |
| 650 | 7 | |a Mifepristone |2 NLM | |
| 650 | 7 | |a 320T6RNW1F |2 NLM | |
| 650 | 7 | |a metapristone |2 NLM | |
| 650 | 7 | |a K1P8OGJ86J |2 NLM | |
| 700 | 1 | |a Zhu, Yewei |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Suhong |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Cuicui |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Rodney J Y |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Liyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xingtian |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Huo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jichuang |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Xiaohuang |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Lee |e verfasserin |4 aut | |
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