Another major group of substrates are alcohols, be they primary, secondary, or tertiary (Figure 15a). Medicinal examples include oxazepam (UGT1A9, 2B7, and 2B15) and zidovudine (36, Figure 14; UGT2B7). Another important example is that of morphine (41, Figure 16), which is conjugated on its phenolic and secondary alcohol groups to form the 3-O-glucuronide (a weak opiate antagonist) and the 6-O-glucuronide (a strong opiate agonist), respectively.82 Hydroxylamines and hydroxylamides may also form O-glucuronides (Figure 15a). Thus, a few drugs and a number of aromatic amines are known to be N-hydroxylated and then O-glucuronidated. A recent example has been found in the metabolism of a new oral hypoglycemic agent 9-[(1S;2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(1-piperazinyl) purine.83 When administered to monkeys, more than half of a dose was recovered as a compound found to be the O-glucuronide of the N-hydroxylated metabolite (42, Figure 16).
An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.
Second in importance to O-glucuronides are the N-glucuronides (Figure 15b) formed from carboxamides and sulfonamides, aromatic and pyridine-type amines, and basic amines.86 The glucuronidation of primary and secondary amides and amines yields the 'plain' N-glucuronides; these will be discussed first, followed by the quaternary N-glucuronides derived from tertiary amines.
The N-glucuronidation of carboxamides is exemplified by the primary amide carbamazepine (19, Figure 9; X = >NCONH2) and by the secondary amide phenytoin (45, Figure 16). The reaction has beneficial significance for
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