The impact of nicotine exposure on the pharmacokinetics and pharmacodynamics of chlorpyrifos: implications for drug/chemical mixtures.
Lee-S; Poet-TS; Busby-AL; Timchalk-C
Toxicologist 2009 Mar; 108(1):117
Chlorpyrifos (CPF) is the most widely used organophosphorus (OP) insecticide to control agricultural pests. CPF is bioactivated mainly in the liver by CYP450-mediated desulfuration to its oxon metabolite (CPF-oxon), which elicits neurotoxicity by inhibiting cholinesterases (ChE). CPF also undergoes dearylation to form 3,5,6- trichloro-2-pyridinol (TCPy). The routine use of tobacco products may modify key metabolizing systems which will further impact the metabolism of OPs. The objective of this study was to evaluate the impact of repeated nicotine administration on CPF pharmacokinetics and pharmacodynamics in male S-D rats. The influence of repeated nicotine exposure on in vivo metabolism of CPF and the level of inhibition in ChE activities in plasma, brain and diaphragm were investigated. Animals (250-300 g) were administered 1) both 1 mg nicotine/kg/day (s.c. at nape) and 5 mg CPF/kg/day (in corn oil, po) for 7 days, 2) 1 mg nicotine/kg/day for 7 days and a single dose of 35 mg CPF/kg (po) on 7th day, no-nicotine-controls were given 3) 5 mg CPF/kg/day for 7 days, or 4) 35 mg CPF/kg once. All the animals were sacrificed at 1, 4, 8, 12 or 24 hr post-last dosing of CPF. For both (single and repeated) CPF exposures, Cmax and AUC of blood TCP were increased (approximately 2-fold) indicating a possible increase of CYP450-mediated metabolism of CPF to TCPy, which is consistent with previous in vitro data. The most significant changes in ChE activities due to nicotine pretreatments were in the brain following the daily administration of 5 mg CPF/kg, where less inhibition of ChE in the brain from nicotine groups (approximately 71% of naive [no CPF, no nicotine]) over chlorpyrifos-only controls (approximately 42% of naive) were observed. But there were no differences in plasma and diaphragm ChE activities due to nicotine pretreatment. The results of this study suggest that repeated nicotine exposure (i.e., from smoking) could alter the metabolism and pharmacodynamics of CPF.
Absorption-rates; Agricultural-industry; Agricultural-chemicals; Biological-effects; Biological-factors; Chemical-hypersensitivity; Chemical-reactions; Dose-response; Exposure-assessment; Exposure-levels; Exposure-methods; Mathematical-models; Metabolic-activation; Neurotoxicity; Neurotoxins; Pesticides-and-agricultural-chemicals; Statistical-analysis; Tobacco; Exposure-levels
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland
Battelle Memorial Institute, Richland, Washington