Kinetics of Toxic Doses of Paraquat and the Effects of Hemoperfusion in the Dog

Abstract

Knowledge of the kinetics of an intoxicant is required for designing potential therapies in poisoned patients. In the case of paraquat, elucidating the kinetics has been made difficult by the paraquat-induced renal failure and the consequent dose and time-dependent elimination of the herbicide. In the current study, we have modelled the plasma and urinary concentrations of paraquat in dogs given a toxic dose, the elimination of which was nonlinear. This enabled us, in turn, to simulate the apparent concentrations of paraquat in the deep tissue compartment, part of which is constituted by the major target organ for paraquat toxicity, the lung. Finally, we defined conditions, if any, under which charcoal hemoperfusion could reduce exposure of the deep compartment to paraquat by ≥ 25%. We found that the plasma concentrations of paraquat could be described by a two compartment model with non-linear elimination from the central compartment. Use of a three compartment model did not improve the fit over that for a two compartment. The volume of distribution of paraquat at steady state approximated that of total body water. Simulated hemoperfusion performed for eight or eighty hours did not reduce exposure of the deep compartment to paraquat by ≥ 25%, unless begun at times ≤ two hours of the infusion commencing. This is consistent with our experimental data in the dog. The lack of efficacy of hemoperfusion is due to the rapid renal elimination of most of the absorbed dose of paraquat over the first 12 hours after its administration, and the later limitation of the rate of removal of paraquat from the body by the slow efflux rate from the deep to central compartment.

KEY WORDS:

• paraquat
• dogs
• hemoperfusion
• pharmacokinetics
• metabolic clearance rate
• herbicides
• models
• biological