Absorption, distribution, metabolism, and excretion of N,N-diethyl-M-toluamide in the rat.
This study was conducted to evaluate the pharmacokinetic parameters of absorption, distribution, metabolism, and excretion (ADME) of the personal insect repellent N,N-diethyl-m-toluamide (DEET) after oral or dermal administration of [14C]DEET in the rat. Six experiments were conducted using separate groups, each consisting of five male and five female rats. Three experiments involved the determination of ADME patterns after oral administration of [14C]DEET as: 1) a single low dose (100 mg DEET/kg body weight); 2) a single high dose (500 mg DEET/kg body weight); and 3) a repeated low dose (100 mg DEET/kg body weight daily for 14 days). A fourth experiment involved the determination of ADME patterns after dermal administration of [14C]DEET at a single low dose of 100 mg DEET/kg body weight. In these four experiments, urine and feces were collected over a 7-day posttreatment period, after which time the animals were euthanized and selected tissues and organs were harvested. Urine, feces, and tissues were analyzed for total 14C content. The major urinary metabolites were identified, and the urinary metabolic profile for each dosage regimen was determined. The remaining two experiments examined the distribution of radioactivity in tissues of animals euthanized at peak 14C blood levels after receiving a single oral low dose or a dermal low dose. In the three experiments designed to determine the ADME patterns of DEET after oral administration, 85-91% of the administered radioactivity was found in the urine and 3-5% was found in the feces. The overall quantitative pattern of excretion of radioactivity into the urine and feces was similar for males and females in the three groups; however, the rate at which the radioactivity was excreted into the urine differed noticeably between individual oral dosing regimens. The fastest rate was observed in the repeated oral low-dose group, followed by the single oral low-dose and the single oral high-dose groups. In the group of rats that received the dermal low dose, 74-78% of the administered dose was found in the urine and 4-7% was found in the feces. An additional 6.5% was found on the surface of the skin at the application site or in association with the occlusive enclosure. The rate of absorption and subsequent excretion of administered radioactivity into the urine and feces was much slower after dermal administration than after all oral dosing regimens. Total tissue residues of 14C activity at 7 days ranged from 0.15 to 0.67% of the administered dose for all dosage regimens. At peak 14C blood levels, the percentages of administered dose reaching the systemic circulation and total 14C tissue residues were significantly higher in the group of animals administered [14C]DEET orally vs. the animals administered [14C]DEET by the dermal route of administration. In both cases, the only tissues with 14C residues consistently higher than that of plasma were the liver, kidney, and fat. HPLC analysis of urine from rats in the ADME phase of the study showed that DEET was metabolized completely in all treatment groups, with little or no parent compound excreted in the urine. Two major urinary metabolites were identified by mass spectroscopy. In both metabolites, the aromatic methyl substituent in the DEET molecule was oxidized to a carboxylic acid moiety. One of the metabolites also had undergone N-dealkylation of an ethyl substituent on the amide moiety.
Schoenig
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GP
Toxicology/Regulatory Services, Inc., Charlottesville, VA 22911, USA.
Hartnagel
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RE
Osimitz
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TG
Llanso
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S
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D003671:DEET / Q000378:metabolism / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D005069:Evaluation Studies as Topic; D005260:Female; D007302:Insect Repellents / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D014018:Tissue Distribution
D007302:Insect Repellents; D003671:DEET