Gearhart J M, Jepson G W, Clewell H J, Andersen M E, Conolly R B
NSI Technology Services Corporation, Dayton, Ohio 45431.
Toxicol Appl Pharmacol. 1990 Nov;106(2):295-310. doi: 10.1016/0041-008x(90)90249-t.
Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would expedite OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed in mammals. DFP tissue:blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate expected in vivo pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain were successfully simulated after a single iv injection (B.R. Martin, 1985, Toxicol. Appl. Pharmacol. 77, 275-284). AChE inhibition and AChE resynthesis data from this study were also simulated. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain (H. Michalek, A. Meneguz, and G.M. Bisso, 1982, Arch. Toxicol., Suppl. 5, 116-119; M.E. Traina and L.A. Serpietri, 1984, Biochem. Pharmacol. 33, 645-653) were also simulated well, but the return of brain AChE activity to basal levels after cessation of repeated dosing was not as well described. The initial model structure returned brain AChE activity to the original level, while in the laboratory studies brain AChE never returned to basal levels, even at 35 days after the last dose. These data suggest modulation of AChE synthesis with prolonged DFP exposure. This study demonstrated the possibility of using a model based on mammalian physiology and biochemistry to simulate in vivo data on DFP pharmacokinetics and AChE inhibition. Scaling of the model between rats and mice was also successful. The approach holds promise for predictive simulation of organophosphate-mediated AChE inhibition in humans.
高剂量接触有机磷酸酯（OP）可致命，而低剂量可能会损害关键任务的执行能力。预测实际接触情况下此类影响的能力将加快OP风险评估。为此，在哺乳动物中建立了基于生理学的二异丙基氟磷酸酯（DFP）药代动力学和乙酰胆碱酯酶（AChE）抑制模型。在大鼠组织匀浆中测定了DFP的组织：血液分配系数、酯酶对DFP的水解速率以及DFP-酯酶双分子抑制速率常数。使用标准的异速生长关系对大鼠和小鼠的其他模型参数进行了缩放。这些DFP特异性参数值与模型一起用于模拟小鼠和大鼠体内预期的药代动力学数据。文献数据用于模型验证。单次静脉注射后成功模拟了小鼠血浆和脑中的DFP浓度（B.R. Martin，1985年，《毒理学与应用药理学》77卷，275 - 284页）。本研究中的AChE抑制和AChE再合成数据也得到了模拟。重复皮下注射DFP对大鼠血浆和脑中AChE活性的影响（H. Michalek、A. Meneguz和G.M. Bisso，1982年，《毒理学档案》，增刊5，116 - 119页；M.E. Traina和L.A. Serpietri，1984年，《生化药理学》33卷，645 - 653页）也得到了较好的模拟，但重复给药停止后脑中AChE活性恢复到基础水平的情况描述得不太好。最初的模型结构使脑中AChE活性恢复到原始水平，而在实验室研究中，即使在最后一剂后35天，脑中AChE也从未恢复到基础水平。这些数据表明长期接触DFP会对AChE合成产生调节作用。本研究证明了使用基于哺乳动物生理学和生物化学的模型来模拟DFP药代动力学和AChE抑制的体内数据的可能性。在大鼠和小鼠之间对模型进行缩放也很成功。该方法有望用于预测模拟有机磷酸酯介导的人类AChE抑制。
