Variability of the in vivo metabolism of clozapine.
OBJECTIVE
Clozapine, the gold standard of antipsychotic treatment in treatment-refractory patients with schizophrenia, is metabolized in vivo to clozapine-N-oxide and N-desmethylclozapine (NDMC = norclozapine). N-desmethylclozapine is an active metabolite of clozapine and combines unique pharmacological properties. Because little is known about the rate of metabolic conversion of clozapine in vivo, we assessed the association between clozapine dose and plasma levels for clozapine and NDMC.


METHODS
Plasma levels of clozapine and NDMC were measured in 485 blood samples from 108 patients with schizophrenia treated with clozapine. %NDMC, the ratio of NDMC to total clozapine (NDMC + clozapine), was used as a measure of the in vivo metabolism of clozapine.


RESULTS
Daily clozapine doses correlated significantly with clozapine levels and NDMC levels, whereas %NDMC showed a weaker negative correlation with clozapine dose. The mean %NDMC value was 37.0% +/- 16.8%, with high variability between subjects. Repeated measurements in subjects treated with the same dose of clozapine showed a high within-subject variability of %NDMC.


CONCLUSIONS
Our results suggest a high degree of between-subject and within-subject variability in the metabolism of clozapine in vivo. Direct administration of NDMC may be preferable to reliably achieve sufficient plasma levels of this compound.
Raedler
Thomas J
TJ
Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. thomas.raedler@calgaryhealthregion.ca
Hinkelmann
Kim
K
Wiedemann
Klaus
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D003024:Clozapine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012559:Schizophrenia / Q000378:metabolism; D055815:Young Adult
D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine