Abstract
Deltamethrin (DLM) is a relatively potent and widely used pyrethroid insecticide. Inefficient detoxification has been proposed to be the primary reason for the greater sensitivity of immature rats to the acute neurotoxicity of DLM. The objective of this study was to test this hypothesis by characterizing the age dependence of DLM metabolism in vitro, as well as toxic signs and blood levels of the neurotoxic parent compound following administration of 10 mg DLM/kg p.o. in glycerol formal. Metabolism was quantified in vitro by monitoring the disappearance of the parent compound from plasma [via carboxylesterases (CaEs)] and liver microsomes [via CaEs and cytochromes P450 (P450s)] obtained from 10-, 21-, and 40-day-old male Sprague-Dawley rats. Mean (±S.E.) intrinsic clearances (Vmax/Km) in these respective age groups by liver P450s (4.99 ± 0.32, 16.99 ± 1.85, and 38.45 ± 7.03) and by liver CaEs (0.34 ± 0.05, 1.77 ± 0.38, and 2.53 ± 0.19) and plasma CaEs (0.39 ± 0.06, 0.80 ± 0.09, and 2.28 ± 0.56) increased significantly (p ≤ 0.05) with age, because of progressive increases in Vmax. Intrinsic clearance of DLM by plasma CaEs and liver P450s reached adult levels by 40 days, but clearance by liver CaEs did not. Hepatic P450s played the predominant role in DLM biotransformation in young and adult rats. The incidence and severity of neurotoxic effects varied inversely with age. Correspondingly, blood DLM areas under the concentration versus time curve (AUCs) and Cmax values progressively decreased with increasing age. Internal exposure to DLM (blood AUCs) was closely correlated with toxic signs (salivation and tremors). The present study provides evidence that the limited metabolic capacity of immature rats contributes to elevated systemic exposure and ensuing neurotoxic effects of DLM.
Footnotes
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This project was supported by EPA STAR Grant R830800. This research has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007807.
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ABBREVIATIONS: DLM, deltamethrin; GI, gastrointestinal; P450, cytochrome P450; AUC, area under the curve; CaE, carboxylesterase; HPLC, high performance liquid chromatography; PBPK, physiologically based pharmacokinetic; iso-OMPA, tetra isopropyl pyrophosphoramide; SD, Sprague-Dawley; PND, postnatal day; AUC, area under the concentration versus time curve; ANOVA, analysis of variance.
- Received October 10, 2005.
- Accepted November 30, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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