Glucuronidation foreign compounds

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. 

Metabolism of foreign compounds is not necessarily detoxication. This has already been indicated in examples and will become more apparent later in this book. This may involve activation by a phase 1 or phase 2 pathway or transport to a particular site followed by metabolism. Thus, sulphate conjugation and acetylation may be involved in the metabolic activation of /V-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of /1-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

Metabolic Stability Metabolic stability assays are the most widely used in vitro ADME screening assay. Metabolism is the body s major mechanism of detoxification of foreign compounds (xenobiotics) such as drug molecules. Common metabolic reactions can be categorized as (1) phase I reactions, which are direct modifications such as oxidation and (2) phase II reactions, which are conjugations such as glucuronidation. As a result of these metabolic conversions, xenobiotics become polar metabolites which can be cleared more... 

Species differences in the metabolism of drugs and other foreign compounds are known to occur (see Williams, 1967 Smith, 1968) and this can affect the amount of a compound excreted in the bile. Thus, in the domestic cat, glucuronide formation is at a low level compared with other species (Robinson and Williams, 1958). The poor ability of the cat to form glu-curonides is apparently due to a deficiency of glucuronyl transferase (Dutton and Gniig, 1957). This enzyme catalyzes the following reaction ... 

D-Glucuronic acid is widely distributed in both the plant and animal worlds. In humans, it is an important component of the acidic polysaccharides of connective tissues. The body also uses it to detoxify foreign phenols and alcohols. In the liver, these compounds are converted to glycosides of glucuronic acid (glucuronides), to be excreted in the urine. The intravenous anesthetic propofol (Problem 10.43), for example, is converted to the following water-soluble glucuronide and then excreted in the urine ... 

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