Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate.

ABSTRACT

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 tissueblood 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.