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Vol. 26, Issue 9, 830-837, September 1998
Drug Metabolism and Drug Disposition Research Group, College of
Pharmacy and Nutrition, University of
Saskatchewan
Glucuronidation of either an aliphatic or aromatic tertiary amine
group in a molecule results in a quaternary ammonium-linked glucuronide metabolite (i.e. N+-glucuronide).
The development of sound information on
N+-glucuronide metabolites, including their
characterization, has been slow. In part, this is because the presence
of both the carboxylic acid group and cationic center in their
structure imparts physiochemical properties such that procedures used
in their analysis, including extraction, require judicious selection.
The techniques used in the identification of
N+-glucuronide metabolites and those
metabolites identified in human urine are the focus of this review.
Especially useful in their identification are the availability of an
authentic synthetic sample and the use of mass spectrometry and nuclear
magnetic resonance (NMR) techniques that, in the first instance,
involve atmospheric pressure ionization or fast atom bombardment modes
of ionization and high-resolution 1H NMR. More than 30 N+-glucuronide metabolites of xenobiotics have
been identified in human urine. In particular,
N+-glucuronidation is a common phenomenon in
the metabolism of H1 antihistamine and antidepressant drugs
with an aliphatic tertiary amine group. Those marketed drugs in which
the reported N+-glucuronide mean urinary
excretion of the orally administered dose exceeds 10% include
cyclizine, cyclobenzaprine, cyproheptadine, dothiepin, doxepin,
ketotifen, lamotrigine, mianserin, and tioconazole. The pharmacological
importance of N+-glucuronidation has not been
clarified.
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