REVERSIBLE METABOLISM OF CLOZAPINE AND CLOZAPINE N-OXIDE IN SCHIZOPHRENIC-PATIENTS

1. To characterize the interconversion process between clozapine and i ts metabolite clozapine N-oxide (CNO), eight healthy male schizophreni cs were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the in terconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were simila r to the values obtained by the usual model-independent method of phar macokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the oth er clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24 .4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twi ce the amount. of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. D CLOZ plasma concentrations were detected in all patients upon clozapin e administration. Upon CNO administration, only one patient had detect able plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients .