Hydroxylation, carbamate metabolism

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]. 

Insecticidal carbamates also inhibit the enzyme acetylcholinesterase by transferring a carbamoyl group to the active hydroxyl. However, they differ from the phosphates in that they inhibit the enzyme reversibly and so a better fit at the active site is required for high activity. In consequence, a narrower range of structures is active. The chemistry, biochemistry, metabolism and toxicology of carbamate insecticides have been thoroughly reviewed (B-76MI10702). 

When taken with meals, a 30% increase in absorption of the drug was observed, with peak plasma concentrations occurring within 2.5-4 h after oral administration. When coadministered with ritonavir, the overall half-life is improved to 15 h.20 Darunavir (1) has been shown to be metabolized by liver enzyme CYP450 (3A4).21 22 Thus when administered with low-dose ritonavir—a CYP450 and protease inhibitor—bioavailability increases from 37% to 84%. Absorption of darunavir occurs primarily in the intestine through passive intracellular diffusion. Darunavir and its metabolites are excreted primarily in the feces and urine.23 Metabolism occurs via, carbamate hydrolysis, aliphatic hydroxylation, aromatic hydroxylation, and other metabolites. 

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)... 

Methocarbamol, USP. Methocarbamol. 3-(o-me-thoxyphcnoxy)-l.2-pn>panediol l-carbamate (Robaxin). is said to be more. sustained in effect than mephenesin. Likely sites for metabolic attack inciude the secondary hydroxyl group and the two ring positions opposite the ether functions. The dihydric parent compound, guaifenesin, is u.sed as an expectorant. 

The relative amounts of the N-depropyl EPTC both early in the incubation period and later suggest that hydroxylation of the a-propyl carbon of the N,N-dialkyl moiety is a major route in the microbial metabolism of EPTC. Hydroxylation of the other carbons of the N,N-dialkyl portion of the carbamate was found to be a less preferred route compared to the hydroxylation of the a-propyl carbon. Sulfoxidation of the carbamate may be second in the importance to the hydroxylation reactions observed. 

Carbonic acid (H2CO3) is formed when carbon dioxide dissolves in water. Although carbonic acid itself is always in equilibrium with carbon dioxide and water, it has several important stable derivatives. Carbonate esters are diesters of carbonic acid, with two alkoxy groups replacing the hydroxyl groups of carbonic acid. Ureas are diamides of carbonic acid, with two nitrogen atoms bonded to the carbonyl group. The unsubstituted urea, simply called urem, is the waste product excreted by mammals from the metabolism of excess protein. Carbamate esters (urethanes) are the stable esters of the unstable carbamic acid, the monoamide of carbonic acid. 

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