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Pharmacopsychiatry 2002; 35(3): 90-95
DOI: 10.1055/s-2002-31516
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Uptake of Clozapine into HL-60 Promyelocytic Leukaemia Cells

U.  Henning, S.  Löffler, K.  Krieger, A.  Klimke
  • 1Neurobiochemical Research Unit, Department of Psychiatry (Head: Prof. Dr. W. Gaebel),
    Heinrich Heine University, Düsseldorf, Germany
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Publication Date:
23 May 2002 (online)

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The atypical antipsychotic, clozapine, exerts superior efficacy in therapy-resistant schizophrenia, but unfortunately induces agranulocytosis with an incidence of 0.8 - 1 %. In this study, we investigated the cellular uptake of clozapine into human promyelocytic leukaemia HL-60 cells using HPLC with electrochemical detection. On incubation with 1.25 to 40 µM clozapine for 30 min, a saturable, energy- and temperature-dependent uptake process takes place (Km = 18.8 µM, kcat = 1.36 nmol/5 min/mg protein at 37° C). This suggests membrane passage of clozapine by a carrier mechanism. 10 µM Indatraline, an inhibitor of dopamine, noradrenaline and serotonin (5-HT) reuptake, but not the selective 5-HT reuptake inhibitor fluvoxamine, markedly reduced the transport of clozapine by 62 %, whereas addition of 10 mM glucose to the incubation medium increased intracellular clozapine concentrations by 28 %. Since cyclosporine A, vinblastine or verapamil up to a final concentration of 10 µM did not alter the intracellular accumulation of clozapine, an involvement of P-glycoprotein seems to be unlikely. In summary, clozapine uptake into HL-60 cells meets criteria of an active unidirectional transport. Its molecular correlates remain to be established.