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In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine\u2009+\u2009methadone (QTP\u2009+\u2009MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC\u2013MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225\u2013296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP\u2009+\u2009MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.<\/jats:p>","DOI":"10.1007\/s00204-023-03620-2","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T14:02:32Z","timestamp":1698069752000},"page":"289-301","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined in vivo metabolic effects of quetiapine and methadone in brain and blood of rats"],"prefix":"10.1007","volume":"98","author":[{"given":"Laura Smedegaard","family":"Heisel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freja Drost","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0255-5889","authenticated-orcid":false,"given":"S\u00e2mia","family":"Joca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lambert Kristiansen","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Simonsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5928-9238","authenticated-orcid":false,"given":"J\u00f8rgen Bo","family":"Hasselstr\u00f8m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-6519","authenticated-orcid":false,"given":"Charlotte Uggerh\u00f8j","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5955-6156","authenticated-orcid":false,"given":"Kirstine Lykke","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"issue":"6","key":"3620_CR1","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1111\/jnc.14446","volume":"146","author":"H Al Feteisi","year":"2018","unstructured":"Al Feteisi H, Al-Majdoub ZM, Achour B, Couto N, Rostami-Hodjegan A, Barber J (2018) Identification and quantification of blood\u2013brain barrier transporters in isolated rat brain microvessels. 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