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Olanzapine 10-N-glucuronide. A tertiary N-glucuronide unique to humans
K Kassahun1, E Mattiuz, R Franklin
1Department of Drug Disposition, Lilly Research Laboratories, USA.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|September 12, 1998
Summary
A novel N-glucuronide metabolite of olanzapine was identified in humans, unexpectedly linked to the benzodiazepine nucleus. This phase 2 metabolite, found in plasma and urine, offers new insights into olanzapine metabolism.
Area of Science:
- Pharmacology
- Drug Metabolism
- Medicinal Chemistry
Background:
- Olanzapine is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.
- Understanding drug metabolism is crucial for optimizing therapeutic efficacy and safety.
Purpose of the Study:
- To identify and characterize major metabolites of olanzapine in human plasma and urine.
- To elucidate the metabolic pathway involving N-glucuronidation of olanzapine.
Main Methods:
- Analysis of human plasma and urine samples.
- Chemical derivatization using phenylisothiocyanate.
- Mass spectrometry and nuclear magnetic resonance (NMR) studies.
- Synthesis of the identified metabolite for confirmation.
Main Results:
- A major metabolite was identified as an N-glucuronide of olanzapine.
- The glucuronic acid moiety was unexpectedly linked to the N-10 position of the benzodiazepine nucleus.
- This N-10 glucuronide was detected in human samples but not in rodents or monkeys, with a trace in dogs.
- The metabolite was stable to enzymatic and base hydrolysis but cleaved under acidic conditions.
Conclusions:
- The formation of an N-glucuronide directly on the benzodiazepine nucleus of olanzapine is a previously unreported metabolic pathway.
- This unique metabolic route provides new information on olanzapine's biotransformation in humans.