title: Olanzapine 10-N-glucuronide. A tertiary N-glucuronide unique to humans.
abstract: In humans, a major metabolite of the atypical antipsychotic olanzapine in the plasma and in the urine was found to be an N-glucuronide. Unexpectedly, the glucuronic acid moiety was linked through a nitrogen of the benzodiazepine nucleus of olanzapine by way of a secondary amine linkage, rather than through a nitrogen on the piperazine substituent of the nucleus, to give a quaternary ammonium glucuronide. Derivatization with phenylisothiocyanate to yield a thiourea adduct indicated that conjugation occurred via a secondary amine. Subsequently, mass spectrometry and nuclear magnetic resonance studies with the isolated metabolite and later with the synthesized metabolite indicated that the glucuronide was linked at the 10- position of olanzapine. This phase 2 metabolite was only detected in the plasma and urine of human subjects and not in mice, rats, or monkeys; a trace of this metabolite was detected in dog urine. The N-10 glucuronide was resistant to enzymatic and base hydrolysis but was cleaved under acidic conditions. Formation of an N-glucuronide metabolite directly with the benzodiazepine nucleus has not previously been reported.
authors.affiliation: Department of Drug Disposition, Lilly Research Laboratories, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kassahun
authors.forename: E
authors.initials: E
authors.lastname: Mattiuz
authors.forename: R
authors.initials: R
authors.lastname: Franklin
authors.forename: T
authors.initials: T
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001569:Benzodiazepines; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D005965:Glucuronates; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine