OLANZAPINE 10-N-GLUCURONIDE - A TERTIARY N-GLUCURONIDE UNIQUE TO HUMANS

In humans, a major metabolite of the atypical antipsychotic olanzapine in the plasma and in the urine was found to be an N-glucuronide. Unex pectedly, the glucuronic acid moiety was linked through a nitrogen of the benzodiazepine nucleus of olanzapine by way of a secondary amine l inkage, rather than through a nitrogen on the piperazine substituent o f the nucleus, to give a quaternary ammonium glucuronide. Derivatizati on with phenylisothiocyanate to yield a thiourea adduct indicated that conjugation occurred via a secondary amine, Subsequently, mass spectr ometry and nuclear magnetic resonance studies with the isolated metabo lite and later with the synthesized metabolite indicated that the gluc uronide was linked at the 10- position of olanzapine, This phase 2 met abolite was only detected in the plasma and urine of human subjects an d not in mice, rats, or monkeys; a trace of this metabolite was detect ed in dog urine. The N-10 glucuronide was resistant to enzymatic and b ase hydrolysis but was cleaved under acidic conditions. Formation of a n N-glucuronide metabolite directly with the benrodiazepine nucleus ha s not previously been reported.