Pond S M, Rivory L P, Hampson E C, Roberts M S
University of Queensland Department of Medicine, Princess Alexandra Hospital, Brisbane, Australia.
J Toxicol Clin Toxicol. 1993;31(2):229-46. doi: 10.3109/15563659309000391.
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 > or = 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 > or = 25%, unless begun at times < or = 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.
为中毒患者设计潜在治疗方案需要了解毒物的动力学。就百草枯而言，百草枯诱发的肾衰竭以及随后除草剂剂量和时间依赖性的消除使得阐明其动力学变得困难。在当前研究中，我们对给予中毒剂量百草枯的犬的血浆和尿液浓度进行了建模，其消除呈非线性。这进而使我们能够模拟百草枯在深部组织隔室中的表观浓度，其中一部分由百草枯毒性的主要靶器官肺构成。最后，我们确定了在何种条件下（如果存在）血液灌流活性炭可使深部隔室对百草枯的暴露降低≥25%。我们发现百草枯的血浆浓度可用一个二室模型来描述，该模型从中央隔室呈非线性消除。使用三室模型并没有比二室模型更好地拟合。百草枯稳态时的分布容积近似于总体液量。除非在输注开始后≤2小时开始，否则进行8小时或80小时的模拟血液灌流并不能使深部隔室对百草枯的暴露降低≥25%。这与我们在犬身上的实验数据一致。血液灌流无效是由于百草枯给药后最初12小时内大部分吸收剂量经肾脏快速消除，以及随后深部隔室向中央隔室的缓慢流出速率限制了百草枯从体内的清除速率。
