{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:15:43Z","timestamp":1758845743970,"version":"3.44.0"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["PCN Reports"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Clozapine is an atypical antipsychotic drug that is most effective against treatment\u2010resistant 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\u2010desmethylclozapine and clozapine N\u2010oxide) in Japanese patients with schizophrenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNA was isolated from the peripheral blood samples of 27 patients with schizophrenia receiving clozapine maintenance treatment, and the pharmacokinetics\u2010related genes (<jats:italic>CYP1A2<\/jats:italic>, <jats:italic>CYP2B6<\/jats:italic>, <jats:italic>CYP2C19<\/jats:italic>, <jats:italic>CYP2D6<\/jats:italic>, <jats:italic>CYP3A5<\/jats:italic>, <jats:italic>ABCG2<\/jats:italic>, and <jats:italic>SLCO1B1<\/jats:italic>) were genotyped. The plasma concentrations of clozapine, N\u2010desmethylclozapine, and clozapine N\u2010oxide were measured using liquid chromatography\u2013tandem mass spectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The plasma concentrations of clozapine and its two major metabolites, N\u2010desmethylclozapine and clozapine\u2010N\u2010oxide, showed significant positive correlations with the daily dose. Neither age nor sex substantially influenced the dose\u2010adjusted 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): <jats:italic>1A2<\/jats:italic>, <jats:italic>CYP2B6<\/jats:italic>, <jats:italic>CYP2C19<\/jats:italic>, <jats:italic>CYP2D6<\/jats:italic>, <jats:italic>CYP3A5<\/jats:italic>, and <jats:italic>ABCG2<\/jats:italic>. In contrast, the dose\u2010adjusted plasma concentration of N\u2010desmethylclozapine was significantly higher in patients with the <jats:italic>SLCO1B1<\/jats:italic> 521C allele than in those with the 521T\/T genotype; the concentrations of clozapine and clozapine N\u2010oxide were not affected by the genetic polymorphisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>SLCO1B1<\/jats:italic> T521C polymorphism may strongly impact the pharmacokinetics of N\u2010desmethylclozapine, a major metabolite of clozapine. Therefore, the <jats:italic>SLCO1B1<\/jats:italic> polymorphisms and plasma levels of N\u2010desmethylclozapine as well as clozapine in patients with schizophrenia should be assayed for optimizing clozapine therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pcn5.70164","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:49:36Z","timestamp":1753883376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Influence of pharmacokinetics\u2010related gene polymorphisms on plasma levels of clozapine and its metabolites in Japanese patients with schizophrenia"],"prefix":"10.1002","volume":"4","author":[{"given":"Shinya","family":"Kinoshita","sequence":"first","affiliation":[{"name":"Department of Neuropsychiatry, Faculty of Medicine Osaka Medical and Pharmaceutical University Takatsuki Osaka 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