Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and in vitro drug-drug interaction potentials

The aim of this study was to determine pharmacokinetics of alpha-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 alpha-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 alpha-amanitin via the renal route (32.6%). After the po administration of alpha-amanitin at doses of 2, 5, or 10 mg/kg to mice, the absolute bioavailability of alpha-amanitin was 3.5-4.8%. Due to this low bioavailability, 72.5% of the po administered alpha-amanitin was recovered from the feces. When alpha-amanitin is administered po, the tissue to plasma area under the curve ratio was higher in stomach > large intestine > small intestine > lung similar to kidneys > liver but not detected in brain, heart, and spleen. The high distribution of alpha-amanitin to intestine, kidneys, and liver is in agreement with the previously reported major intoxicated organs following acute alpha-amanitin exposure. In addition, alpha-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 alpha-amanitin exposure.

Automated summary

This study aimed to determine the pharmacokinetics of alpha-amanitin in mice after intravenous or oral administration. Results showed rapid clearance and major excretion via the renal route after intravenous injection, and low bioavailability and high recovery from feces after oral administration. The distribution to intestine, kidneys, and liver was consistent with previously reported major intoxicated organs. Data also suggested potential remote drug interaction with alpha-amanitin exposure.