Drugs from almost all therapeutic classes are glucuronidated. For those having narrow therapeutic indices (e.g. morphine, chloramphenicol), glucuronidation is therefore likely to have important consequences in their clinical use. The different isoenzymes of the UGT family have high organ specificity locations: for example, bilirubin UGT is highly expressed in human liver, but is absent in human kidney, whereas phenol UGT is highly expressed in both organs. Individual UGTs are subject to differential induction by hormones, leading to tissue-specific regulated expression. In addition, the spectrum of UGTs in different tissues can be differentially altered by exposure to drugs and other xenobiotics. Glucuronidation requires an adequate supply of UDPGA and its concentration in cytosol may determine the transferase activity. This may be more critical in extrahepatic tissues than in the liver.

The concentration of UDPGA in the kidney has been estimated to be one-fifteenth that in the liver in humans. As mentioned above, the glucuronidation mechanism involves a nucleophilic substitution, illustrated in for a phenol as substrate. The resultant glucuronide has the ȕ-configuration at the C-1 atom of the glucuronic acid. With the attachment of the hydrophilic carbohydrate moiety, containing an easily ionisable carboxyl group, a lipid-soluble compound is thus converted into a conjugate that is poorly reabsorbed by the renal tubules from the urine, and therefore more rapidly excreted, predominantly via the kidneys. Nonetheless, it should be noted that certain high molecular weight glucuronides are excreted via the bile into the gastrointestinal tract where subsequent hydrolysis may result in reabsorption of drug or metabolites (biliary recirculation) or excretion in the faeces.

As seen from the latter figure, alcohols and phenols form ether glucuronides; aromatic and some aliphatic carboxylic acids form ester (acyl) glucuronides; aromatic amines form N-glucuronides, and thiol compounds form S-glucuronides, both of these being more labile to acid than are the O-glucuronides. Some tertiary amines have been found to form quaternary ammonium N-glucuronides. Compounds containing a 1,3-dicarbonyl system (e.g. phenylbutazone) can form C-glucuronides by direct conjugation, bypassing prior metabolism. The degree of C-glucuronide formation is determined by the acidity of the functional group separating the carbonyl groups. Drug-acyl glucuronides are reactive conjugates at physiological pH. The acyl group of the C1 -acyl glucuronide can migrate via transesterification from the original C-1 position of the glucuronic acid to the C-2, C-3, or C-4 positions.

The resulting positional isomers are not hydrolysable by ȕ-glucuronidase. Under physiological or weakly alkaline conditions, however, the C1 -acyl glucuronide can hydrolyse in the urine to the parent compound (aglycone) or effect acyl migration to an acceptor macromolecule. The pH-catalysed migration of the acyl group from the drug C1 -Oacyl glucuronide to a protein or other cellular constituent occurs with the formation of a covalent bond to the protein. Further details of this process are given below. Endogenous compounds undergoing glucuronoconjugation include steroids, bilirubin and thyroxine. In the case of bilirubin, this pathway of detoxification is a major one, mediated by UGTs located in numerous tissues.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access