title: Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration.
abstract: 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.
authors.affiliation: Battelle Memorial Institute, Pacific Northwest Division, Richland, Washington 99352, USA. jordan.smith@pnnl.gov
authors.forename: Jordan Ned
authors.initials: JN
authors.lastname: Smith
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Yuehe
authors.initials: Y
authors.lastname: Lin
authors.forename: Elise M
authors.initials: EM
authors.lastname: Klohe
authors.forename: Charles
authors.initials: C
authors.lastname: Timchalk
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000378:metabolism; D001711:Biotransformation; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004784:Environmental Monitoring / Q000379:methods; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010575:Pesticides / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D011728:Pyridones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012463:Saliva / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D010575:Pesticides; D011728:Pyridones; C012587:3,5,6-trichloro-2-pyridinol; D002802:Cholinesterases; D004390:Chlorpyrifos