TY - JOUR T1 - Tertiary <em>N</em>-Glucuronides of Clozapine and Its Metabolite Desmethylclozapine in Patient Urine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1343 LP - 1348 VL - 29 IS - 10 AU - Ursula Breyer-Pfaff AU - Helmut Wachsmuth Y1 - 2001/10/01 UR - http://dmd.aspetjournals.org/content/29/10/1343.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -