4.7 Article

Toxicokinetics of β-Amanitin in Mice and In Vitro Drug-Drug Interaction Potential

期刊

PHARMACEUTICS
卷 14, 期 4, 页码 -

出版社

MDPI
DOI: 10.3390/pharmaceutics14040774

关键词

beta-amanitin; mouse; toxicokinetics; tissue distribution; drug interaction; drug-metabolizing enzymes; drug transporters

资金

  1. National Research Foundation of Korea (NRF) - Korea government (MSIT) [NRF-2020R1A2C2008461, NRF2020R1A4A2002894]

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The toxicokinetics of beta-amanitin, a toxic compound found in Amanitaceae mushrooms, were studied in mice. The compound was rapidly eliminated from plasma and mainly excreted through feces after oral administration. It distributed predominantly in the intestines and stomach.
The toxicokinetics of beta-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 mg/kg. beta-amanitin disappeared rapidly from plasma with a half-life of 18.3-33.6 min, and 52.3% of the iv dose was recovered as a parent form. After oral administration, the AUC again increased in proportion with doses of 2, 5, and 10 mg/kg. Absolute bioavailability was 7.3-9.4%, which resulted in 72.4% of fecal recovery from orally administered beta-amanitin. Tissue-to-plasma AUC ratios of orally administered beta-amanitin were the highest in the intestine and stomach. It also readily distributed to kidney > spleen > lung > liver approximate to heart. Distribution to intestines, kidneys, and the liver is in agreement with previously reported target organs after acute amatoxin poisoning. In addition, beta-amanitin weakly or negligibly inhibited major cytochrome P450 and 5 '-diphospho-glucuronosyltransferase activities in human liver microsomes and suppressed drug transport functions in mammalian cells that overexpress transporters, suggesting the remote drug interaction potentials caused by beta-amanitin exposure.

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