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 pg/kg DFP and at 24 hr after acute doses of DFP (10-54 pg/kg), as well as for repeated DFP exposures. The PBPK model for DFP was also adapted for the purpose of modeling parathion, including its metabolism to the toxic daughter product paraoxon. The development and validation of this PBPK model for two OPs provides a basis for studying the kinetics and in vivo metabolism of other bioactivated organophosphate pesticides and their pharmacodynamic effect in humans. -Environ Health Perspect 102(Suppl 11):51-60 (1994)

Adenosine A1Receptor AgonistN6-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

“…They turned out to be negligible relative to the value of 0.13 Ϯ 0.02 and 0.06 Ϯ 0.01 min Ϫ1 for the elimination rates k1 irr and k2 irr . The synthesis and elimination constants of AChE are estimated to be 3.2 ⅐ 10 Ϫ5 nmol/ min and 1.7 ⅐ 10 Ϫ3 min Ϫ1 in rat plasma and 2.3 ⅐ 10 Ϫ5 nmol/min and 1.7 ⅐ 10 Ϫ4 min Ϫ1 in rat brain, respectively (Wenthold et al, 1974;Gearhart et al, 1994). This directly implies that the shape of the inhibitory profile is only dependent on the interaction of sarin with the AChE, reflected by the elimination rate constant k irr , and the concentration of sarin at the site of action.…”

Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.

“…The 100 ng/kg DFP dose presents 16 pmol to a 30-g mouse whose blood volume is 1.3-1.6 mL (21), for a maximum blood concentration of 11 nM. This represents just 0.001% of the Michaelis-Menten concentration of DFP metabolism in mouse blood and tissue (22), allowing linear modeling that assumes the concentrations of metabolic enzymes remain essentially unchanged by this dose throughout the exposure and clearance. The measurements and model represent the regeneration and elimination of the enzyme-substrate pair, as neither the metabolized free DPA nor the recycled protein components are able to further label proteins.…”

“…However, the rapid metabolism of DFP argues for some sort of chemical or physical protection of the fluorine during this delay. The lipid partition coefficient for DFP is more than 10 times that for liver, kidney, and perfused tissue (22), so the assumed model of lipid storage delay is plausible; however, the compartment may also represent a delayed chemical interaction.…”

WinPBPK-A Software for Physiologically-based Pharmacokinetic Model Analysis: Application to Tissue and Organ Distribution Analysis of Tacrolimus.

“…The system was applied to the physiologi cally-based pharmacokinetic analysis of an immunosup pressant, tacrolimus, and good correlations were ob tained between the simulated image autoradiograms and the real autoradiograms. where i=3, 4,6,7,8,9,11,12,13,14,15,16,17 …”