In vitro metabolism of clozapine in human hepatic microsomes

B. G. Augustin, A. Thurston, G. Thomas, J. Hui, M. W. Jann

Research output: Contribution to journalArticlepeer-review


Purpose: Clozapine is an atypical antipsychotic used to treat refractory schizophrenics. Clozapine forms two major metabolites, N-desmethyl-clozapine, and Clozapine N-oxide. The CYP450 3A4 and 1A2 isozymes have been shown to be involved with clozapine's metabolism. The purpose of this study is to characterize the metabolism of clozapine to it's major metabolites with in vitro P450 models by utilization of microsomes, and to identify the effects of known 1A2 inhibitors on the this metabolic process. Methods: Microsomes were isolated from human liver tissue. Clozapine was exposed to microsomes and 1A2 inhibitor (furafylline) for incubation periods of one and two hours. NADP+, Glucose-6-phosphate, and Glucose-6-phosphate dehydrogenase served as the energy source. Clozapine and metabolites were assayed by HPLC. Results: Peak heights for clozapine at incubations of 1 and 2 hours were: 997.458 and 973.112 respectively. Peak heights for clozapine controls at incubations of 1 and 2 hours were: 2352.477 and 2075.38 respectively. Peak heights for clozapine incubations with furafylline at 1 hour was: 1269.58. Conclusions: Clozapine is readily metabolized by in vitro microsome preparations. Clozapine metabolism in vitro was shown to be inhibited by furafylline. In vitro models can be used to predict clinically significant drug interactions with clozapine.

Original languageEnglish
Pages (from-to)179
Number of pages1
JournalClinical Pharmacology and Therapeutics
Issue number2
StatePublished - 1997


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