Influence of pharmacokinetics-related gene polymorphisms on plasma levels of clozapine and its metabolites in Japanese patients with schizophrenia.

AIM: Clozapine is an atypical antipsychotic drug that is most effective against treatment-resistant schizophrenia and causes serious adverse effects, including agranulocytosis. We examined the relationships between age, sex, genetic polymorphisms, and the plasma concentrations of clozapine and its metabolites (N-desmethylclozapine and clozapine N-oxide) in Japanese patients with schizophrenia.

METHODS

DNA was isolated from the peripheral blood samples of 27 patients with schizophrenia receiving clozapine maintenance treatment, and the pharmacokinetics-related genes (CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A5, ABCG2, and SLCO1B1) were genotyped. The plasma concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were measured using liquid chromatography-tandem mass spectrometry.

RESULTS

The plasma concentrations of clozapine and its two major metabolites, N-desmethylclozapine and clozapine-N-oxide, showed significant positive correlations with the daily dose. Neither age nor sex substantially influenced the dose-adjusted plasma concentrations of clozapine or its two metabolites. The plasma concentrations of clozapine and its two metabolites did not notably differ among the genotypes of cytochrome P450 (CYP): 1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A5, and ABCG2. In contrast, the dose-adjusted plasma concentration of N-desmethylclozapine was significantly higher in patients with the SLCO1B1 521C allele than in those with the 521T/T genotype; the concentrations of clozapine and clozapine N-oxide were not affected by the genetic polymorphisms.

CONCLUSION

The SLCO1B1 T521C polymorphism may strongly impact the pharmacokinetics of N-desmethylclozapine, a major metabolite of clozapine. Therefore, the SLCO1B1 polymorphisms and plasma levels of N-desmethylclozapine as well as clozapine in patients with schizophrenia should be assayed for optimizing clozapine therapy.