1. Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and
- Author
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Ria, Park, Won-Gu, Choi, Min Seo, Lee, Yong-Yeon, Cho, Joo Young, Lee, Han Chang, Kang, Chang Hwan, Sohn, Im-Sook, Song, and Hye Suk, Lee
- Subjects
Male ,Mice ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,Liver ,Microsomes ,Animals ,Humans ,Drug Interactions ,Mass Spectrometry ,Poisons ,Alpha-Amanitin ,Chromatography, Liquid - Abstract
The aim of this study was to determine pharmacokinetics of α-amanitin, a toxic bicyclic octapeptide isolated from the poisonous mushrooms, following intravenous (iv) or oral (po) administration in mice using a newly developed and validated liquid chromatography-high resolution mass spectrometry. The iv injected α-amanitin disappeared rapidly from the plasma with high a clearance rate (26.9-30.4 ml/min/kg) at 0.1, 0.2, or 0.4 mg/kg doses, which was consistent with a rapid and a major excretion of α-amanitin via the renal route (32.6%). After the po administration of α-amanitin at doses of 2, 5, or 10 mg/kg to mice, the absolute bioavailability of α-amanitin was 3.5-4.8%. Due to this low bioavailability, 72.5% of the po administered α-amanitin was recovered from the feces. When α-amanitin is administered po, the tissue to plasma area under the curve ratio was higher in stomachlarge intestinesmall intestinelung ~ kidneysliver but not detected in brain, heart, and spleen. The high distribution of α-amanitin to intestine, kidneys, and liver is in agreement with the previously reported major intoxicated organs following acute α-amanitin exposure. In addition, α-amanitin weakly or negligibly inhibited cytochrome P450 and 5'-diphospho-glucuronosyltransferase enzymes activity in human liver microsomes as well as major drug transport functions in mammalian cells overexpressing transporters. Data suggested remote drug interaction potential may be associated with α-amanitin exposure.
- Published
- 2021