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Research ArticleArticle

Tertiary N-Glucuronides of Clozapine and Its Metabolite Desmethylclozapine in Patient Urine

Ursula Breyer-Pfaff and Helmut Wachsmuth
Drug Metabolism and Disposition October 2001, 29 (10) 1343-1348;
Ursula Breyer-Pfaff
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Helmut Wachsmuth
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Abstract

In experiments with expressed human UDP-glucuronosyltransferase 1A4 (UGT1A4), the antipsychotic clozapine proved to be conjugated to two different glucuronides, one of which was identified as the quaternary ammonium glucuronide derivatized at theN-methylpiperazine group; this compound had previously been isolated from patient urine. An additional glucuronide produced in larger quantity was assumed to be conjugated at the secondary nitrogen of the central ring to form 5-N-glucuronide, but this was not proven. The analogous olanzapine 10-N-glucuronide was found to make a major contribution to urinary metabolites in human volunteers. In the present investigation, tertiary 5-N-glucuronides were isolated from incubations of clozapine and desmethylclozapine with human liver microsomes fortified with UDP-glucuronic acid, and their structures were confirmed by mass and 1H NMR spectrometry. The same conjugates could also be purified from patient urine. Their approximate quantities in urine from four patients ranged between 0.1 and 0.5% of the dose, as did those of the quaternary ammonium glucuronide of clozapine. Analogous to olanzapine 10-N-glucuronide, the tertiary clozapine 5-N-glucuronide was resistant toward enzymatic hydrolysis but was labile under acidic conditions.

Footnotes

  • Abbreviations used are::
    HPLC
    high-pressure liquid chromatography
    MES
    4-morpholineethanesulfonic acid
    ESI
    electrospray ionization
    CID
    collision-induced dissociation
    amu
    atomic mass unit
    MS
    mass spectroscopy
    • Received April 11, 2001.
    • Accepted June 29, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Research ArticleArticle

Tertiary N-Glucuronides of Clozapine and Its Metabolite Desmethylclozapine in Patient Urine

Ursula Breyer-Pfaff and Helmut Wachsmuth
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1343-1348;

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Research ArticleArticle

Tertiary N-Glucuronides of Clozapine and Its Metabolite Desmethylclozapine in Patient Urine

Ursula Breyer-Pfaff and Helmut Wachsmuth
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1343-1348;
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