Pharmacokinetics of clozapine and its metabolites in hippocampal HT22 cells.
Up to now, it is not yet clear whether and how clozapine and its metabolites are metabolized in neuronal cells. The interconversion of clozapine and its metabolites, clozapine-N-oxide and norclozapine, was studied in the hippocampal neuronal in vitro system of HT22 cells. Clinically relevant concentrations of clozapine (200+400 ng/ml) and its metabolites (100+200 ng/ml) were used for the examination of the metabolizing effects after short- (4 h) and long- (24 h) term incubation. Two-way analysis of variance revealed a significant decrease of clozapine (P<0.01) and norclozapine (P<0.01) levels in the supernatants of HT22 cells after the treatment procedures. Student-Newman-Keuls tests showed a significant decrease of clozapine 400 after 24 h of incubation (P=0.01) as well as of all concentrations of norclozapine. No significant treatment effects were found for the clozapine-N-oxide degradation. Using semi-quantification by reverse transcriptase-polymerase chain reaction methods, we could show a significant increase of cytochrome P450 (CYP) 1A2 mRNA levels (P<0.05) after clozapine treatment with 200 ng/ml. The results of the present study strongly suggest that clozapine and norclozapine are metabolized in hippocampal neuronal HT22 cells by CYP1A2, whereas the levels of clozapine-N-oxide were not affected. Moreover, CYP1A2 mRNA levels were significantly changed by incubation with clozapine 200.
Heiser
Philip
P
Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University of Marburg, Hans-Sachs-Str 6, 35037 Marburg, Germany. heiser@mailer.uni-marburg.de
Schüler-Springorum
M
M
Schulte
Eva
E
Hausmann
Christiane
C
Remschmidt
Helmut
H
Krieg
Jürgen-Christian
JC
Vedder
Helmut
H
D000704:Analysis of Variance; D001692:Biological Transport; D002478:Cells, Cultured; D003024:Clozapine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; C058272:norclozapine; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine; C079149:clozapine N-oxide