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ONTOGENY OF HEPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN AGE-DEPENDENT ACUTE NEUROTOXICITY.
Citation:
ANAND, S. S., K. KIM, S. J. PADILLA, S. MURALIDHARA, H. J. KIM, J. W. FISHER, AND J. V. BRUCKNER. ONTOGENY OF HEPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN AGE-DEPENDENT ACUTE NEUROTOXICITY. DRUG METABOLISM AND DISPOSITION. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 34(3):389-397, (2006).
Impact/Purpose:
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.
Description:
Deltamethrin is a reltively potent and widely used pyrethroid pesticide that is known to be markedly more toxic to young animals. The data presented in this paper shed light on the mechanisms for this increased sensitivity in the young. Young animals lack the ability to efficiently detoxify deltamethrin via either the P540 route or the plasma or hepatic carboxylesterase route. As they mature the young gradually attain adult levels of detoxification capability, but until they do, they are more sensitive to the acute neurotoxicity of deltamethrin.
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