Effect of In Vivo Nicotine Exposure on Chlorpyrifos Pharmacokinetics and Pharmacodynamics in Rats

Details

• Personal Author:
  Busby-Hjerpe AL ; Lee, Stephen A. ; Poet TS ; Smith JN ; Timchalk C
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Biochemistry Chemistry Energy Metabolism Environmental Monitoring Environmental Pollution Hypersensitivity Insecticides Laboratories Microbiology Nicotine Occupational Health Respiratory System Safety

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• Keywords:
  Author Keywords: Chlorpyrifos Biological-effects Chemical-hypersensitivity Chemical-reactions Cholinesterase Dose-response Environmental-contamination Exposure-assessment Exposure-levels Exposure-methods Inhalation-studies Insect-repellents Laboratory-animals Laboratory-testing Metabolic-activation Metabolic-study Metabolism Microchemistry Microscopic-analysis Organophosphorus Pesticide PBPK Pesticides Pharmacodynamics Physiological-factors Statistical-analysis

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• ISSN:
  0009-2797
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 10 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  449-457
• Volume:
  184
• Issue:
  3
• NIOSHTIC Number:
  nn:20036818
• Citation:
  Chem-Biol Interact 2010 Mar; 184(3):449-457
• Contact Point Address:
  Pacific Northwest National Laboratory, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352
• Email:
  charles.timchalk@pnl.gov
• Federal Fiscal Year:
  2010
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods
• Performing Organization:
  Battelle Memorial Institute, Richland, Washington
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Chemico-Biological Interactions
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7a081a711d7226f0f4530700685ec25de893cbf9a70e7450c658e5c07b1f2477b837297216f1dd69889090d34daae097d9579d3780d81e840d75b84affb59674
• Download URL:
  https://stacks.cdc.gov/view/cdc/188077/cdc_188077_DS1.pdf
• File Type:
  [PDF - 814.79 KB ]