Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat.
Timchalk-C; Campbell-JA; Busby-AL; Smith-JN; Lee-S; Poet-TS; Barr-DB
Toxicologist 2010 Mar; 114(1):402
Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2- pyridinol (TCPy) are products of both in vivo metabolism and environmental degradation of the insecticide chlorpyrifos (CPF) and are routine urinary biomarkers of exposure. However, biomonitoring of TCPy, DEP and DETP may be reflective of an individual's contact with both the parent pesticide and exposure to these metabolites in the environment. In the current study, simultaneous dosing of 13Cor 2H- isotopically labeled CPF (13C-labeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to compare the pharmacokinetics of CPF with TCPy, and DETP. The study objective was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Individual metabolites were co-administered (gavage) with the parent compound at equal molar doses (14 micromol/kg; ~5mg/kg CPF). Major differences in the pharmacokinetics between CPF and metabolite doses were observed within the first 3 h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (>/=3 h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or 2H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact their pharmacokinetics.
Biological-effects; Biological-factors; Biological-systems; Biomarkers; Chemical-hypersensitivity; Chemical-reactions; Environmental-exposure; Exposure-assessment; Exposure-levels; Exposure-limits; Exposure-methods; Insecticides; In-vivo-studies; Laboratory-animals; Pesticides; Pharmacodynamics; Quantitative-analysis
Agriculture, Forestry and Fishing; Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah
Battelle Pacific Northwest Laboratories