RAPID FORMATION OF CLOZAPINE IN GUINEA-PIGS AND MAN FOLLOWING CLOZAPINE-N-OXIDE ADMINISTRATION

Clozapine and its metabolite clozapine-N-oxide (0.5 mg/kg) were admini stered intraperitoneally to guinea-pigs. Significant amounts of clozap ine were detected in plasma, liver, frontal cortex and caudate after c lozapine-N-oxide administration. The amount of clozapine detected in p lasma two hours post-administration of N-oxide was approximately 40% o f the amount of clozapine after clozapine injection. Tissue concentrat ions of clozapine in liver, frontal cortex and caudate were greater th an plasma concentrations. Clozapine concentrations were almost equival ent in the liver. Clozapine concentrations after N-oxide injection wer e approximately 40-50% lower compared to clozapine concentrations afte r clozapine administration in the frontal cortex and caudate. A single dose of clozapine-N-oxide was given to a schizophrenic patient. Cloza pine plasma concentrations were detected after N-oxide administration. This study shows that clozapine is formed from its N-oxide metabolite and that a reversible metabolic pathway exists for clozapine and cloz apine-N-oxide.