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Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats.

Authors
Lee-S; Poet-TS; Smith-JN; Busby-Hjerpe-AL; Timchalk-C
Source
Chem-Biol Interact 2010 Mar; 184(3):449-457
NIOSHTIC No.
20036818
Abstract
Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1mg nicotine/kg or saline, and to either a single oral dose of 35mg CPF/kg or a repeated dose of 5mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy peak concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine within the first 24-h post last dose. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. A physiologically based pharmacokinetic model for CPF was used to simulate the effect of increasing the dearylation V(max) based upon previously conducted in vitro metabolism studies. Predicted CPF-oxon concentrations in blood and brain were lower following the expected V(max) increase in nicotine treated groups. These model results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, resulting in altered brain AChE inhibition.
Keywords
Biochemistry; Biological-effects; Chemical-hypersensitivity; Chemical-reactions; Dose-response; Environmental-contamination; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Insecticides; Insect-repellents; Laboratory-animals; Laboratory-testing; Metabolic-activation; Metabolic-study; Metabolism; Microbiology; Microchemistry; Microscopic-analysis; Pesticides; Pharmacodynamics; Physiological-factors; Statistical-analysis; Author Keywords: Chlorpyrifos; Organophosphorus pesticide; Metabolism; Nicotine; PBPK; Cholinesterase
Contact
Pacific Northwest National Laboratory, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352
CODEN
CBINA8
Publication Date
20100330
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Type
Grant
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
Issue of Publication
3
ISSN
0009-2797
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Chemico-Biological Interactions
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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