N+-glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group.
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.
Hawes
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Drug Metabolism and Drug Disposition Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Canada.
D000588:Amines / Q000378:metabolism*; D000818:Animals; D005965:Glucuronates / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D000588:Amines; D005965:Glucuronates; D004364:Pharmaceutical Preparations; D015262:Xenobiotics