title: Uptake of clozapine into HL-60 promyelocytic leukaemia cells.
abstract: 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 microM clozapine for 30 min, a saturable, energy- and temperature-dependent uptake process takes place (K m = 18.8 microM, k cat = 1.36 nmol/5 min/mg protein at 37 degrees C). This suggests membrane passage of clozapine by a carrier mechanism. 10 microM 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 microM 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.
authors.affiliation: Neurobiochemical Research Unit, Department of Psychiatry (Head: Prof. Dr. W. Gaebel), Heinrich Heine University, Düsseldorf, Germany. KN27120@mail.lvr.de
authors.forename: U
authors.initials: U
authors.lastname: Henning
authors.forename: S
authors.initials: S
authors.lastname: Löffler
authors.forename: K
authors.initials: K
authors.lastname: Krieger
authors.forename: A
authors.initials: A
authors.lastname: Klimke
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine