• Korean Journal of Biological Psychiatry
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• v.13 no.3
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• pp.152-161
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• 2006

Objective : The relationship between the total daily dose of clozapine given and the plasma concentrations of clozapine and its metabolites(N-desmethylclozapine and clozapine N-oxide) and the effect of Glu158Lys (wild-type : Glu, 'H' ; variant : Lys, 'h') and Glu308Gly(wild-type : Glu, 'D' ; variant : Lys, 'd') variation in FMO3 gene on plasma concentrations of clozapine and its metabolites was studied in schizophrenic patients. Methods : Trough plasma concentrations of clozapine and its metabolites were measured in 34 schizophrenic patients receiving clozapine. The genetic variation of 'h' and 'd' in FMO3 were analyzed in 21 among 34 patients. Results : A linear relationship between the total daily dose of clozapine given(mg/kg body weight per day) and the plasma concentrations(nM) of clozapine was revealed by regression analysis(p<0.001) in the 23 patients receiving a constant daily dose of clozapine for 8 days. The plasma molar concentration ratios of clozapine N-oxide/clozapine in 8 subjects with 'hh' or 'Hh' alleles were not different from those in 6 subjects with 'HH' alleles and the plasma molar concentration ratios in 6 subjects with 'dd' or 'Dd' alleles were not different from those in 8 subjects with 'DD' alleles. Conclusion : The effect of Glu158Lys and Glu308Gly variation in FMO3 gene on clozapine metabolism could not be shown.

• The Korean Journal of Pharmacology
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• v.30 no.3
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• pp.343-349
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• 1994

A number of neurological syndromes(e.g. tardive dyskinesia) are developed as a consequence of chronic treatment with neuroleptics or antipsychotic agents. Despite the long and succesful use of phenothiazine derivatives and related agents in the treatment of certain states of mental disease, the mechanisms of these drugs are still poorly understood. One current hypothesis from extensive reviews is that these compounds might significantly interfere with the cyclic nucleotide system in brain (Levin and Weiss, 1977; Nowicki et al., 1991; Haley et al., 1992). Nitric oxide (NO), one of an interesting messenger molecule and aberrant transmitter, is believed to play a important role in biological functions of cyclic nucleotides in nervous system. It has been reported that calcium-dependent NO synthesis in endothelial cytosol is mediated by calmodulin which is supposed to be tightly related to pharmacological actions of antipsychotic agents. In the present study, the effect of several antipsychotic agents on the activity of NO synthesis and formation of cyclic GMP were investigated. These agents inhibited both the formation of $[^3H]L-citrulline$ and that of $[^3H]cyclic$ GMP by concentration-dependent manner, and their inhibiting patterns are so similar to that of calmodulin antagonist.