Toxic effects, pharmacokinetics and clearance of saxitoxin, a component ofparalytic shellfish poison (PSP), in cats

Saxitoxin (STX) was the first known and most studied toxic component of par alytic shellfish poisoning (PSP). This toxin blocks neuronal transmission b y binding to the voltage-gated Na+ channel. Although the toxin's mechanism of action is well known at the molecular level, there are still many unreso lved questions about its pharmacokinetics and the PSP intoxication syndrome in mammals. Some of these questions are addressed in the present paper, wh ich describes an experimental design which allowed us to follow the dynamic s of STX poisoning in vivo. Adult cats were anaesthetized and permanently c oupled to artificial ventilation, they were then intravenously injected wit h low (2.7 mu g of STX/kg) and high doses (10 mu g of STX/kg) of toxin. Car diovascular parameters such as blood pressure and electrocardiograms were r ecorded, urine and blood samples were collected during the four hours of ex perimental time. In order to quantify mass amount of STX, we used the post- column derivatization HPLC method. Urine and blood samples were cleansed us ing a C-18 Sep-Pack cartridge and ultrafree microcentrifuge filters. At the end of each experiment, the animals were killed and tissue samples from br ain, liver, spleen and medulla oblongata were extracted to measure the amou nt of STX. As compared to control period. Low doses of STX made no differen ce in hemodynamics parameters. In contrast, high doses drastically reduced blued pressure, produced myocardial failure and finally cardiac arrest. Adm inistration of 2.5 mu g/kg x min of dobutamine restored hemodynamics parame ters and allowed the animal to overcome the shock. With high doses, the cal culated STX renal clearance in cats is 0.81 ml/min x kg(-1). This valued co rresponds to 20.25% of the reported inulin renal clearance. Nevertheless wi th Low doses the STX renal clearance is 3.99 ml/min x kg(-1). This data sug gest that in cats with normal cardiovascular parameters and diuresis, the S TX excretion mainly involves glomerular filtration. During experimental tim e, no PSP toxins other than STX was detected in the body fluids and tissue samples analyzed, indicating that the mammals can not metabolize this molec ule. STX was found in intensely irrigated organs such as the liver and sple en but also in the central nervous system (brain and medulla oblongata), sh owing that STX was capable of crossing the blood-brain barrier. (C) 1999 El sevier Science Ltd. All rights reserved.