Clozapine and its metabolite clozapine-N-oxide (0.5 mg/kg) were administered intraperitoneally to guinea-pigs. Significant amounts of clozapine were detected in plasma, liver, frontal cortex and caudate after clozapine-N-oxide administration. The amount of clozapine detected in plasma two hours post-administration of N-oxide was approximately 40% of the amount of clozapine after clozapine injection. Tissue concentrations of clozapine in liver, frontal cortex and caudate were greater than plasma concentrations. Clozapine concentrations were almost equivalent in the liver. Clozapine concentrations after N-oxide injection were approximately 40-50% lower compared to clozapine concentrations after clozapine administration in the frontal cortex and caudate. A single dose of clozapine-N-oxide was given to a schizophrenic patient. Clozapine 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 clozapine-N-oxide.