Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

Journal Article · Thu May 01 04:00:00 EDT 2008 · NeuroToxicology, 29(3 Sp Iss):428-443

DOI:https://doi.org/10.1016/j.neuro.2008.02.004· OSTI ID:937381

Timchalk, Chuck; Poet, Torka S

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 937381
• Report Number(s): PNNL-SA-58478; 400412000
• Journal Information: NeuroToxicology, 29(3 Sp Iss):428-443, Journal Name: NeuroToxicology, 29(3 Sp Iss):428-443 Journal Issue: 3 Sp Iss Vol. 29; ISSN 0161-813X; ISSN NRTXDN
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ABSORPTION
BINARY MIXTURES
CHOLINESTERASE
DOSIMETRY
IN VITRO
IN VIVO
INSECTICIDES
KINETICS
METABOLISM
METABOLITES
RODENTS
chlorpyrifos
cholinesterase
diazinon
mixtures
organphosphorus insecticide