Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro: role in age-dependent acute neurotoxicity.
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<or=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.
Anand
Sathanandam S
SS
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA. sanand@rx.uga.edu
Kim
Kyu-Bong
KB
Padilla
Stephanie
S
Muralidhara
Srinivasa
S
Kim
Hyo J
HJ
Fisher
Jeffrey W
JW
Bruckner
James V
JV
D000208:Acute Disease; D000375:Aging / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001711:Biotransformation; D043182:Carboxylesterase / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D007306:Insecticides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000097:blood* / Q000209:etiology / Q000378:metabolism; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011722:Pyrethrins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; D003577:Cytochrome P-450 Enzyme System; D043182:Carboxylesterase