Pharmacokinetics of [ 14C]-paraquat and associated biochemical and pathologic changes in beagle dogs following intravenous administration

Abstract

A single toxic dose (25 mg/kg, iv) of [ 14C]-paraquat (PQ) caused vomiting in all six Beagle dogs but mild diarrhea in only two dogs. All dogs manifested salivation and labored breathing within 6 to 9 hours and died between 32 and 36 hours postdose. The activities of plasma lactic dehydrogenase and creatine phosphokinase were generally increased at all times after PQ treatment. The glutamic oxaloacetic transaminase activity was increased at 6, 12, 24 hr and at death. The plasma angiotensin converting enzyme activity was unaffected. The plasma creatinine levels were generally increased and renin levels were increased at 12, 24 hr and at death. The hematocrit and plasma protein were increased at 6, 12 and 24 hr. A significant decrease in plasma K +, Na +, and Cl − was obtained at 6 hr after treatment and continued until death. The plasma concentration time curve showed a biphasic decline with a half life of 42.5 min for the alpha-phase. The distribution volume was 25.8% of body weight. The dogs dying from PQ toxicity showed the highest amount of PQ in bile followed by kidney, lung, liver, spleen, heart, adrenal glands, pancreas, thymus and muscle. Tissue paraquat concentrations in the first three organs correlated well with the severity of pathologic changes induced by this herbicide. The kidney had tubular necrosis characterized by segmental degeneration and coagulation necrosis of epithelium of the proximal convoluted tubules. The lungs showed patchy edema and alveolar hemorrhage. Hepatic changes included hepatocellular vacuolation. It was concluded from this study that secretion of PQ in bile may contribute to the total body clearance of this compound and that renal failure is a major cause of death in dogs acutely poisoned with paraquat.