Kinetics of amatoxins in human poisoning: Therapeutic implications

Abstract

The kinetics of alpha and beta amanitin were studied in 45 patients intoxicated with Amanita Phalloides. The amatoxins were analyzed by high performance liquid chromatography in plasma (43 cases), urine (35 cases), gastroduodenal fluid (12 cases), feces (12 cases) and tissues (4 cases). All patients had gastrointestinal symptoms and 43 developed an acute hepatitis. Two patients underwent successful liver transplantation. Eight patients, of whom three were children, died. The detection of amatoxins in the biological fluids was time dependent. The first sample was obtained at an average of 37.9 h post ingestion in the patients with positive results and at 70.6 h in the samples without detectable amatoxins. Plasma amatoxins were detected in 11 cases at 8 to 190 ng/mL for alpha and between 23.5 to 162 ng/mL for beta. In 23 cases amatoxins were detected in urine with a mean excretion per hour of 32.18 micrograms for alpha and 80.15 micrograms for beta. In 10 patients the total amounts eliminated in the feces (time variable) ranged between 8.4 and 152 micrograms for alpha amanitin and between 4.2 and 6270 micrograms for beta amanitin. In three of four cases amatoxins were still present in the liver and the kidney after day 5. Amatoxins were usually detectable in plasma before 36 h but were present in the urine until day 4. The rapid clearance indicates that enhanced elimination of amatoxins requires early treatment. Clearance of circulating amatoxins by day 4 spares the transplanted liver.

Development, optimization and application of an analytical methodology by ultra performance liquid chromatography–tandem mass spectrometry for determination of amanitins in urine and liver samples

“…The most 65 important route of elimination is renal, since about 80-85% of the amatoxins dose absorbed is 66 excreted in the urine within 6 hours and less than 10% in the bile [6, 15,17]. The early 67 elimination of the amatoxins through the kidney can be explained by the low molecular 68 weight of the toxins, allowing an easy glomerular filtration [15].…”

“…They disappear rapidly from plasma and do not bind to plasma proteins, being free 63 in circulatory system [6,17]. The volume of distribution is close to the extracellular space…”

“…[6, 17,18] and the total body clearance corresponds to the creatinine clearance [17]. The most 65 important route of elimination is renal, since about 80-85% of the amatoxins dose absorbed is 66 excreted in the urine within 6 hours and less than 10% in the bile [6, 15,17].…”

Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with α-amanitin

“…Although in humans intestinal absorption of amanitins is very fast, the onset of clinical symptoms (watery diarrhea, abdominal pain, vomiting) occurs generally 10 -12 h after mushroom ingestion. Therefore, patients with poisoning caused by amatoxin-containing mushroom typically seek medical care at the time when a large portion of toxins had been absorbed from the gastrointestinal tract and uptaked into hepatocytes (Jaeger et al, 1993;Schneider, 2001). The α-AMA uptake by human hepatocytes is mediated by the OATP1B3, a subtype of organic anion−transporting polypeptide located in the plasma membrane (Letschert et al, 2006).…”

“…The inhibitory or competitive OATP1B3 substrates may inhibit α-AMA uptake by human hepatocytes (Letschert et al, 2006). Amanitins, including α-AMA, remain in enterohepatic circulation for four days after mushroom ingestion (Jaeger et al, 1993;Schneider, 2001). (Fraschini et al, 2002).…”