Glucuronidation reactions compounds

Figure 13.21. Major glucuronidation reactions involving phenols, alcohols, carboxylic acids, car-bamic acids, hydroxylamines and hydroxylamides, carboxamides, sulfonamides, various amines, thiols, dithiocarboxylic acids, and 1,3-dicarbonyl compounds.

Formation of. glucuronide conjugates is a major metabolic conversion for many lipid-soluble compounds. The product glucuronides are more water soluble and usually more readily excreted. The glucuronic acid donor in this reaction is... 

Glucuronidation involves the transfer of D-glucuronic acid from UDP-a-glu-curonic acid to an acceptor compound. The family of enzymes which catalyze this reaction are the UDP-glucuronyl transferases [16]. The reaction proceeds by nucleophilic Sn2 substitution of the C-1 carbon of glucuronic acid, the product undergoing inversion of configuration. The mechanism is illustrated schematically in Figure 7.21. 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Both temazepam and lorazepam undergo glucuronidation. The clearance rates for these compounds are lower in women (Divoll et al. 1981 D. J. Greenblatt et al. 1980 R. B. Smith et al. 1983). This is the direction predicted based on animal models (Skett 1988). OCs have been shown to increase the rate of these reactions, and one would expect the elimination half-lives to be briefer in women who are using OCs. In fact, the elimination half-life does decrease in women who take OCs (Patwardhan et al. 1983 Stoehr et al. 1984). 

Figure 7.16 Reaction sequences of uridine diphospho glucuronosyl transferase and chemical structures of compounds that form glucuronides. Arrows indicate the position on each molecule where glucuronidation occurs.

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