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.
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Dr. Uwe Henning
Neurobiochemical Research Unit Department of Psychiatry
Heinrich-Heine-University Düsseldorf
Bergische Landstr. 2
40629 Düsseldorf
Germany
Email: KN27120@mail.lvr.de