Document Detail

Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine.
MedLine Citation:
PMID:  11560879     Owner:  NLM     Status:  MEDLINE    
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 the N-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 (1)H 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.
U Breyer-Pfaff; H Wachsmuth
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  29     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-09-18     Completed Date:  2001-11-01     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1343-8     Citation Subset:  IM    
Department of Toxicology, University of Tuebingen, Tuebingen, Germany.
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MeSH Terms
Chromatography, High Pressure Liquid
Clozapine / analogs & derivatives,  metabolism*,  urine*
Glucuronates / metabolism,  urine*
Glucuronides / chemistry
Hydrogen-Ion Concentration
Microsomes, Liver / metabolism
Reg. No./Substance:
0/Glucuronates; 0/Glucuronides; 0/clozapine N-glucuronide; 5786-21-0/Clozapine

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