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SPECIES DIFFERENCES IN THE IN VITRO METABOLISM OF DELTAMETHRIN AND ESFENVALERATE:DIFFERENTIAL OXIDATIVE AND HYDROLYTIC METABOLISM BY HUMANS AND RATS.
Citation:
GODIN, S., E. SCOLLON, M. F. HUGHES, P. M. POTTER, M. K. ROSS, AND M. J. DEVITO. SPECIES DIFFERENCES IN THE IN VITRO METABOLISM OF DELTAMETHRIN AND ESFENVALERATE:DIFFERENTIAL OXIDATIVE AND HYDROLYTIC METABOLISM BY HUMANS AND RATS. DRUG METABOLISM AND DISPOSITION. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 34(10):1764-71, (2006).
Impact/Purpose:
To examine species differences in the elimination of esfenvalerate and deltamethrin from liver microsomes
Description:
Pyrethroids are neurotoxic pesticides whose pharmacokinetic behavior plays a role in their potency. This study examined the elimination of esfenvalerate and deltamethrin from rat and human liver microsomes. A parent depletion approach in the presence and
absence of NADPH was utilized to assess species differences in biotransformation
pathways, rates of elimination, and intrinsic hepatic clearance. Esfenvalerate was
eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human
liver microsomes. The intrinsic hepatic clearance (CLINT) of esfenvalerate was estimated
to be three- fold greater in rodents than in humans on a per kg body weight basis.
Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism
in rat liver microsomes; however, in human liver microsomes, deltamethrin was
eliminated almost entirely via NADPH-independent hydrolytic metabolism. The CLINT
for deltamethrin was estimated to be two-fold more rapid in humans than in rats on a per
kg body weight basis. Metabolism by purified rat and human carboxylesterases (CEs)
were utilized to further examine the species in hydrolysis of deltamethrin and
esfenvalerate. Results of CE metabolism revealed that human carboxylesterase 1 (hCE-
1) was markedly more active towards deltamethrin than the class 1 rat CEs Hydrolase A
and B and the class 2 human CE (hCE-2); however, Hydrolase A metabolized
esfenvalerate 2-fold faster than hCE-1, while Hydrolase B and hCE-1 hydrolyzed
esfenvalerate at equal rates. These studies demonstrate a significant species difference in
the in vitro pathways of biotransformation of deltamethrin in rat and human liver
microsomes, which is due in part to differences in the intrinsic activities of rat and human
carboxylestersases.