A Tertiary N-Glucuronide Unique to Humans
1996 ASPET N-Glucuronidation of Xenobiotics Symposium
Abstract
In humans, a major metabolite of the atypical antipsychotic olanzapine in the plasma and in the urine was found to be anN-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. TheN-10 glucuronide was resistant to enzymatic and base hydrolysis but was cleaved under acidic conditions. Formation of anN-glucuronide metabolite directly with the benzodiazepine nucleus has not previously been reported.
Footnotes
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Send reprint requests to: Kelem Kassahun, Ph.D., Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486-0004.
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↵1 Current address: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486-0004.
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↵2 Current address: Department of Drug Metabolism and Spectroscopy, Amgen Bio-Pharma, 3200 Walnut Street, Boulder, CO 80303.
- Abbreviations used are::
- HPLC
- high-performance liquid chromatography
- LC-MS
- liquid chromatography-mass spectrometry
- MS
- mass spectrometry
- The American Society for Pharmacology and Experimental Therapeutics
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