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.