Ethyl carbamate , metabolic

V-Ethyl carbamate esters of fenoldopam, used for treatment of acute circulatory failure, provide another example of a carbamate ester prodrug. The intrinsically short half-life and extensive first-pass metabolism of fenoldopam limit its oral administration. /V-Ethyl carbamate esters of fenoldopam provide elevated plasma fenoldopam levels and increases in the renal blood flow of significantly greater duration than when the parent compound is administered orally [30],... 

Miller JA, Miller EC. The metabolic activation and nucleic acid adducts of naturally-occurring carcinogens recent results with ethyl carbamate and the spice flavors safrole and estragole. Br J Cancer 1983 48(1) 1-15. 

The in vivo metabolism of a homologous series of alkyl carbamates (7.2, Fig. 7.3) has yielded some informative results [13]. The hydrolysis of these esters liberates carbamic acid (7.3, Fig. 7.3), which breaks down spontaneously to C02 and NH3, allowing the extent of hydrolysis to be determined conveniently and specifically by monitoring C02 production. When such substrates were administered to rats, there was an inverse relationship between side-chain hydroxylation and ester-bond hydrolysis. Thus, for compounds 12 the contribution of hydrolysis to total metabolism (90 - 95% of dose) decreased in the series R=Et (ca. 85-90%), Bu (ca. 60-65%), hexyl (ca. 45 - 50%), and octyl (ca. 30%). Ethyl carbamate (urethane) is of particular toxicological interest, being a well-established carcinogen in experimental animals. In vitro studies of adduct formation have confirmed the competition between oxidative toxification mediated by CYP2E1 and hydrolytic detoxification mediated by carboxylesterases [14]. 

Second-generation juvenoids incorporate more substantial structural departures from neotenin and are more resistant to metabolic and environmental degradation. Epiphenonane, 2-ethyl-3-[3-ethyl-5-(4-ethylphenoxy)-pent-3-en-yl] 2-methyloxirane (131), has a rat oral LD50 of 4000 mg/kg. It and similar juvenoids are used in China and Japan to prolong the last larval instar of the silkworm so that silk production is increased 10—15%. Fenoxycarb, ethyl [2-(4-phenoxyphenoxy)ethyl] carbamate (132) (mp 53°C, vp 0.0078 mPa at 20°C), is soluble in water to 6 mg/L. The rat oral LD50 is >16,800 mg/kg. Fenoxycarb has a wide spectrum of activity, interfering with the developmental processes of fleas, cockroaches, and ants. 

Animals. The major metabolic path is ring hydroxylation to form ethyl [2- p-(p-hydroxyphenoxy)phenoxy]ethyl]carbamate Plants. Rapidly degraded in plants Soil. Low mobility in soil, no bioaccumulation. Relatively fast degradation. DT50 1.7-2.5 months (lab.), few to 31 days (field)... 

The metabolism of amino acids does not affect the taste, but is problematic at a toxicological level, because it increases the concentrations of biogenic amines and ethyl carbamate precursors in wine. 

Fa-kert, P. G., and Lee, R. P. (1997). Metabolism of ethyl carbamate by pulmonary cytochrome P450 and carboxylesterase isozymes Involvement of CYP2E1 and hydrolase A. Toxicol Appl Pharmacol 146, 245-254. 

Urethan. Carbamic acid ethyl ester ethyl carbamate urethane ethyl urethan. C3H,NO, mol wt 89.09. C 40.44%-, H 7.92%, N 15.72%, O 35.92%,. NH2COOC2H5. Prepd by heating urea with alcohol under pressure by warming urea nitrate with alcohol and sodium nitrite. Toxicity data K. J. Franklin, J, Pharmacol. Exp. Ther. 42, 1 (1931). Review of carcinogenic action and metabolism Mirvish in Advan. Cancer Res 11, 1-42 (1968). 

Kemper, R. A., Myers, S, R.. and Hurst, H. E. (1995). Dcioxificadoii of vinyl carbamate epoxide by glutathione Evidence for participation of glutathione 5-transferases in metabolism of ethyl carbamate. Toxicol Appl Pharmacol 13S, 1 lO-i 18. 

Although the role of cytochrome P450 in the metabolism of carbofuran has not been explored in any system, the metabolism of ethyl carbamate by P450 2EI has been reported by Lee elal. (1998). The study implicated cytochrome P450 2EI and carboxylcsterase enzyme in the metabolism of carcinogens such as ethyl carbamate in the murine liver microsomal system. The fish taken from a lake in Newfoundland with a history of hydrocarbon pollution showed increased AHH activity (Payne and Penrose, 1975). Thus, many workers have studied the EROD activity of fish in laboratory conditions or naturally exposed samples as a molecular biomarker for aquatic pollution. These studies are reviewed by Whyte etal. (2000) and Goldfarb el al. (1998), In addition, EROD activity in carbofuran-lreated fish has been measured in laboratory conditions. 

In addition to the parent fenoxycarb, residue methods for the two major metabolic products Ro-16-8797 CGA-294850, ethyl lV-2-[4-(4-hydroxyphenoxy) phenoxyethyljcarbamate, MW= 317.3 and Ro-17-3192 CGA-294851, (2-hydroxyethyl)-A-2-[4-(4-hydroxyphenoxy)phenoxyethyl]carbamate, MW = 333.3 in animal by-products were also developed. 

K. F. Thomsen, F. Strpm, B. V. Sforzini, M. Begtrup, N. Mprk, Evaluation of Phenyl Carbamates of Ethyl Diamines as Cyclization-Activated Prodrug Forms for Protecting Phenols against First-Pass Metabolism , Int. J. Pharm. 1994, 112, 143-152. 

Investigation of the metabolic fate of compounds 64b and 71b led to the following results After peroral administration of 71b in rats, about 90% of the ingested silicon could be detected in urine within 4 days. In the ethyl ether extract of the urine, no unchanged 71b could be found. In the ethyl acetate extract the dealkylation product 85 was detected (29% of ingested sila-carbamate 71b) ... 

Thomsen, K.F. Strom, F. Sforzini, B.V. Begtrup, M. Mprk, N. Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism. Int. J. Pharma. 1994, 112, 143-152. 

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