N-GLUCURONIDATION, A COMMON PATHWAY IN HUMAN METABOLISM OF DRUGS WITHA TERTIARY AMINE GROUP()

Glucuronidation of either an aliphatic or aromatic tertiary amine grou p in a molecule results in a quaternary ammonium-linked glucuronide me tabolite (i.e. N+-glucuronide). The development of sound information o n N+-glucuronide metabolites, including their characterization, has be en slow. In part, this is because the presence of both the carboxylic acid group and cationic center in their structure imparts physiochemic al properties such that procedures used in their analysis, including e xtraction, require judicious selection. The techniques used in the ide ntification of N+-glucuronide metabolites and those metabolites identi fied in human urine are the focus of this review. Especially useful in their identification are the availability of an authentic synthetic s ample and the use of mass spectrometry and nuclear magnetic resonance (NMR) techniques that, in the first instance, involve atmospheric pres sure ionization or fast atom bombardment modes of ionization and high- resolution H-1 NMR. More than 30 N+-glucuronide metabolites of xenobio tics have been identified in human urine. In particular, N+-glucuronid ation is a common phenomenon in the metabolism of H-1 antihistamine an d antidepressant drugs with an aliphatic tertiary amine group. Those m arketed drugs in which the reported N+-glucuronide mean urinary excret ion of the orally administered dose exceeds 10% include cyclizine, cyc lobenzaprine, cyproheptadine, dothiepin, doxepin, ketotifen, lamotrigi ne, mianserin, and tioconazole. The pharmacological importance of N+-g lucuronidation has not been clarified.