Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats |
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| Authors: | Sookwang Lee Torka S Poet Jordan N Smith Andrea L Busby-Hjerpe Charles Timchalk |
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| Institution: | 1. CIIMAR/CIMAR – Interdisciplinary Centre of Marine and Environmental Research, Laboratory of Environmental Toxicology, University of Porto, Rua dos Bragas, 289, 4050-123, Porto, Portugal;2. CIIMAR/CIMAR – Interdisciplinary Centre of Marine and Environmental Research, Laboratory of Ecophysiology, University of Porto, Rua dos Bragas, 289, 4050-123, Porto, Portugal;3. ICBAS/UP – Institute of Biomedical Sciences Abel Salazar, University of Porto, Largo Professor Abel Salazar, 2, 4099-003, Porto, Portugal;1. Institute of Anatomy, Otto von Guericke University Magdeburg, D-39120, Magdeburg, Germany;2. Institute of Anatomy and Cell Biology, University of Würzburg, D-97070, Würzburg, Germany;3. Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, USA;1. Department of Microbiology and Immunology, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan;2. Hououdou Co. Ltd., 4-3-2 Ebara, Shinagawa-ku, Tokyo 142-0063, Japan;1. The Third Central Clinical College of Tianjin Medical University, Tianjin, China;2. The Key Laboratory of Artificial Cells, Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, China;3. Department of Hepatobiliary Surgery, The Third Central Hospital of Tianjin, Tianjin, China;4. Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA |
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| Abstract: | 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 1 mg nicotine/kg or saline, and to either a single oral dose of 35 mg CPF/kg or a repeated dose of 5 mg 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 Vmax based upon previously conducted in vitro metabolism studies. Predicted CPF-oxon concentrations in blood and brain were lower following the expected Vmax 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. |
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