PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR THE INHIBITION OF ACETYLCHOLINESTERASE BY ORGANOPHOSPHATE ESTERS

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 greatly improve O P risk assessment. To this end, a physiologically based model for diis opropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. DFP tissue/blood partition coefficie nts, rates of DFP hydrolysis by esterases. and DFP-esterase bimolecula r inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard a llometric relationships, These DFP-specific parameter values were used with the model to simulate pharmacokinetic data from mice and rats. l iterature data were used for model validation. DFP concentrations in m ouse plasma and brain, as weil as AChE inhibition and AChE resynthesis data, were successfully simulated for a single iv injection. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma an d brain were also well simulated except for an apparent decrease in ba sal AChE activity in the brain which persisted 35 days after the last dose. The psychologically based pharmacokinetic (PBPK) model parameter values specific for DFP in humans, for example. tissue/blood partitio n coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and b imolecular inhibition rate constants for target enzymes were scaled fr om rodent data or obtained from the literature Good agreement was obta ined between model predictions and human exposure data on the inhibiti on of red blood cell AChE and plasma butyrylcholinesterase after an in tramuscular injection of 33 mu g/kg DFP and at 24 hr after acute doses of DFP (10-54 mu g/kg), as well as for repeated DFP exposures. The PB PK model for DFP was also adapted for the purpose of modeling parathio n, including its metabolism to the toxic daughter product paraoxon. Th e development and validation of this PBPK model for two OPs provides a basis for studying the kinetics and in vivo metabolism of other bioac tivated organophosphate pesticides and their pharmacodynamic effect in humans.