title: Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.
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 greatly improve OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. 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 pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain, as well 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 and brain were also well simulated except for an apparent decrease in basal 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 partition coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and bimolecular inhibition rate constants for target enzymes were scaled from rodent data or obtained from the literature. Good agreement was obtained between model predictions and human exposure data on the inhibition of red blood cell AChE and plasma butyrylcholinesterase after an intramuscular injection of 33 micrograms/kg DFP and at 24 hr after acute doses of DFP (10-54 micrograms/kg), as well as for repeated DFP exposures.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Gearhart
authors.forename: G W
authors.initials: GW
authors.lastname: Jepson
authors.forename: H J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
authors.forename: R B
authors.initials: RB
authors.lastname: Conolly
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D006801:Humans; D006868:Hydrolysis; D007531:Isoflurophate / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D008954:Models, Biological; D010261:Paraoxon / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment
chemical_list: D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D000110:Acetylcholinesterase; D010261:Paraoxon