{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:23:04Z","timestamp":1791260584210,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T00:00:00Z","timestamp":1693785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clozapine (CLZ) is extensively used for treatment\u2010resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug\u2013drug interactions (DDIs). In the current report, we present a case of a 35\u2010year\u2010old male non\u2010smoking TRS patient whose steady\u2010state plasma trough concentrations (<jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub>) of CLZ and its active metabolite, <jats:italic>N<\/jats:italic>\u2010desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub> of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2\u2010 and CYP3A4\u2010mediated CLZ metabolism by measuring the formations of NDMC and clozapine <jats:italic>N<\/jats:italic>\u2010oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2\u2010 and CYP3A4\u2010mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with <jats:italic>IC<\/jats:italic><jats:sub>50<\/jats:sub> values for the formations of CNO and NDMC of 2.8\u00a0\u03bcM and 4.1\u00a0\u03bcM, respectively, suggesting that LEM exerts as a potent time\u2010dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co\u2010medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ\u2010related adverse events.<\/jats:p>","DOI":"10.1111\/bcp.15889","type":"journal-article","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T08:00:43Z","timestamp":1692432043000},"page":"354-359","source":"Crossref","is-referenced-by-count":11,"title":["Effect of lemborexant on pharmacokinetics of clozapine: A potential drug\u2013drug interaction mediated by time\u2010dependent inhibition of CYP3A4"],"prefix":"10.1111","volume":"90","author":[{"given":"Kenya","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Pharmacy Fukushima Medical University Hospital  Fukushima 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