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 per sonal insect repellent N,N-diethyl-m-toluamide (DEET) after oral or de rmal administration of [C-14]DEET in the rat. Six experiments were con ducted using separate groups, each consisting of five male and five fe male rats. Three experiments involved the determination of ADME patter ns after oral administration of [C-14]DEET as: 1) a single low dose (1 00 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 [C-14]DEET at a single low dos e of 100 mg DEET/kg body weight, In these four experiments, urine and feces were collected over a 7-day posttreatment period, after which ti me the animals were euthanized and selected tissues and organs were ha rvested, Urine, feces, and tissues were analyzed for total C-14 conten t. The major urinary metabolites were identified, and the urinary meta bolic profile for each dosage regimen was determined. The remaining tw o experiments examined the distribution of radioactivity in tissues of animals euthanized at peak C-14 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 fe males in the three groups; however, the rate at which the radioactivit y was excreted into the urine differed noticeably between individual o ral dosing regimens. The fastest rate was observed in the repeated ora l 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 l ow 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 occlus ive enclosure. The rate of absorption and subsequent excretion of admi nistered radioactivity into the urine and feces was much slower after dermal administration than after all oral dosing regimens. Total tissu e residues of C-14 activity at 7 days ranged from 0.15 to 0.67% of the administered dose for all dosage regimens. At peak C-14 blood levels, the percentages of administered dose reaching the systemic circulatio n and total C-14 tissue residues were significantly higher in the grou p of animals administered [C-14]DEET orally vs. the animals administer ed [C-14]DEET by the dermal route of administration, In both cases, th e only tissues with C-14 residues consistently higher than that of pla sma were the liver, kidney, and fat, HPLC analysis of urine from rats in the ADME phase of the study showed that DEET was metabolized comple tely in all treatment groups, with little or no parent compound excret ed in the urine, Two major urinary metabolites were identified by mass spectroscopy, In both metabolites, the aromatic methyl substituent in the DEBT molecule was oxidized to a carboxy(ic acid moiety, One of th e metabolites also had undergone N-dealkylation of an ethyl substituen t on the amide moiety.