Carbamate ester hydrolysis, rats

Table I. Carbamate Ester Hydrolysis (0-24 Hour) Following Oral Treatment (0.2 Mg/Kg) of Rats Compared with Toxicity...

A situation opposite to that is seen with the carbamate insecticides. As shown in Table I, data from studies in our laboratory demonstrate that carbamate insecticides most toxic to rats are also hydrolyzed at a faster rate. Ester hydrolysis in these studies was measured by quantitation of radioactive carbon dioxide in the respiratory gases of animals treated orally with the carbamate radiolabeled on the carbonyl carbon. Yet, hydrolysis of... 

In similar studies, we have compared the toxicity of the same carbamate insecticide to several laboratory animal species that varied considerably insofar as rates of in vitro ester hydrolysis was concerned. Again, it was the more susceptible species which demonstrated the faster rates of hydrolysis (6). Neither absorption from the gut, or total metabolism as evidenced by excretion rates and metabolites excreted, was significantly different when the same carbamate was administered to either rats, mice, guinea pigs, or gerbils. At this point, it can only be surmised that the same properties that make the carbamates excellent in vivo inhibitors of acetylcholinesterase also make them excellent substrates for other esterases. 

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]. 

T. L. Huang, A. Szekacs, T. Uematsu, E. Kuwano, A. Parkinson, B. D. Hammock, Hydrolysis of Carbonates, Thiocarbonates, Carbamates, and Carboxylic Esters of a-Naph-thol, /LNaphthol, and p-Nitrophenol by Human, Rat, and Mouse Liver Carboxylesterases , Pharm. Res. 1993, 10, 639 - 648. 

Its metabolism in rats was investigated by Menn and co-workers (1976), demonstrating that the activation is initiated by P=S-+P=0 conversion (oxon formation), while detoxification resulted from hydrolysis of the alkyl and aryl phosphate ester group, as well as from cleavage of the C=N and O—C bond of the oxime carbamate moiety. 

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