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Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

We report a new assay to measure the serum concentrations of the atypical antipsychotic drug clozapine and two major metabolites, norclozapine and clozapine-N-oxide. The analytes and an internal standard (triprolidine) were extracted from alkalinized samples into ethyl acetate and back-extracted into 0.1 mol/L HCl. The acid extracts were chromatographed on a reversed-phase liquid chromatographic column with photodiode array detection (210-340 nm). With the 254-nm signal, between-run imprecision (CV) was < 2% for clozapine and norclozapine at 400 micrograms/L, and 4.1% for clozapine-N-oxide at 100 micrograms/L. Absolute recovery exceeded 65%, and the detection limit was approximately 3-4 micrograms/L. In 25 patients at steady state at a mean daily clozapine dosage of 269 mg (3.09 mg/kg), clozapine averaged 231 +/- 144 micrograms/L (mean +/- SD); norclozapine and clozapine-N-oxide concentrations averaged 84% and 23% that of clozapine. Analyte concentrations were significantly correlated with daily dose. The method's ability to quantify clozapine and two major metabolites simultaneously with precision and sensitivity makes it useful in pharmacokinetic studies and therapeutic monitoring.