Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats

Although the action of Gonyautoxins (GTXs) and Saxitoxin (STX) mechanisms is well known at the molecular level, there are still many unresolved questions associated with the intoxication syndrome in mammals. For example, how are these toxins absorbed in the digestive system? Where are they absorbed? What is the absorption rate? What is the maximal concentration in plasma (C-max) and the time taken to reach this C-max (T-max) in the case of oral toxin administration? These questions are addressed in this paper, which describes an experimental design which allowed us to follow the toxicokinetics and toxicodynamics of GTX 2/3 epimers poisoning in vivo, when an oral dose of toxin was administered to an anaesthetized cat permanently coupled to an artificial ventilator. The GTX 2/3 epimers was orally administered with a dose of 70 mug/kg, then urine and blood samples were collected during a 5 h experimental period. The toxins were quantified using a post column derivatisation high performance liquid chromatography method. Procedure of extraction, clean up and detection of GTX 2/3 epimers are described. The arterial pressure of the cats was continuously monitored. The GTX 2/3 epimers oral dose was completely absorbed at intestinal level. This dose was sufficient to decrease arterial pressure and to produce death within the experimental time. However, with the intravenous (i.v.) administration of 2.5 mug/min kg of dobutamine, hemodynamic parameters were restored which allowed the animal to overcome the cardiovascular shock. The renal clearance of GTX 2/3 epimers measured in the cats was 4.6 ml/min kg, indicating that like STX, in cats with normal cardiovascular parameters and diuresis, the GTX 2/3 excretion mainly involves glomerular filtration. Oral doses of 35 mug/kg of GTX 2/3 epimers and plasma level of 36 ng/ml are lethal limits for cats. This is the first report that shows the effects of the GTX 2/3 epimers at different plasmatic levels and their relationship to their toxic effects when they are administered orally, resembling the intoxication illness in mammals. (C) 2002 Elsevier Science Ltd. All rights reserved.