Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration

Jordan Ned Smith; Jun Wang; Yuehe Lin; Elise M Klohe; Charles Timchalk

doi:10.1093/toxsci/kfs251

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Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration

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Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration

Jordan Ned Smith, Jun Wang, Yuehe Lin, Elise M Klohe and Charles Timchalk

Toxicological sciences, Vol.130(2), pp.245-256

12/2012

DOI: https://doi.org/10.1093/toxsci/kfs251

Handle:

https://hdl.handle.net/2376/110204

PMID: 22874420

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Abstract

Cholinesterase Inhibitors - pharmacokinetics

Injections, Intravenous

Area Under Curve

Cholinesterase Inhibitors - blood

Male

Metabolic Clearance Rate

Chlorpyrifos - blood

Dose-Response Relationship, Drug

Biotransformation

Pesticides - pharmacokinetics

Chlorpyrifos - pharmacokinetics

Biomarkers - metabolism

Risk Assessment

Environmental Monitoring - methods

Chlorpyrifos - administration & dosage

Rats

Pesticides - blood

Rats, Sprague-Dawley

Animals

Cholinesterase Inhibitors - administration & dosage

Models, Biological

Saliva - metabolism

Protein Binding

Pyridones - metabolism

Cholinesterases - metabolism

Hydrogen-Ion Concentration

Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluate in vivo pharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5-5mg/kg) and pilocarpine (~13 mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5 mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0-15 min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers.

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Title: Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration
Creators: Jordan Ned Smith - Battelle Memorial Institute, Pacific Northwest Division, Richland, Washington 99352, USA. jordan.smith@pnnl.gov
Jun Wang
Yuehe Lin
Elise M Klohe
Charles Timchalk
Publication Details: Toxicological sciences, Vol.130(2), pp.245-256
Academic Unit: Mechanical and Materials Engineering, School of
Publisher: United States
Grant note: R01 OH008173 / NIOSH CDC HHS R01 OH003629 / NIOSH CDC HHS
Identifiers: 99900547016801842
Language: English
Resource Type: Journal article