Linkage of Diisopropylfluorophosphate exposure and effects in rats using a physiologically based pharmacokinetic and pharmacodynamic model

Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair cognitive performance. Diisopropylfluorophosphate (DFP) is an OP insecticide. The biological response of DFP is primarily mediated through its effects on B-esterases, including acetylcholinesterase (AChE). By binding to AChE, DFP inhibits the function of AChE, resulting in the accumulation of the neurotransmitter acetylcholine at synapses. A model capable of predicting the relationship between DFP exposure and the resultant inhibition of AChE would be useful in risk assessment and the design of medical countermeasures against exposure to B-esterase (BEST) inhibitors. In the present study, we modified a previously- described physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the effect of DFP on (B-EST) activity by the usage of more widely accepted physiological data and description to more accurately simulate the physiological condition. In addition, we edited the mathematical formulas describing the relevant chemical reactions between DFP and B-EST to improve the theoretical model. For model verification, we compared AChE recovery data measured in vivo in male Wistar rats after single and multiple subcutaneous dosages of DFP with our model predictions. Our results showed a closer fit to the experimental data of AChE activity in contrast to the original PBPK/PD model after single and multiple injections of DFP in rats. The results supported the common hypothesis that distinct regeneration-dominated and synthesis-dominated phases of AChE recovery likely occurred during the experiments. Simulation results from the updated model also highlighted the crucial transition time period where additional experimental results would be most helpful in confirming the kinetics of B-EST dissociation and resynthesis.