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.