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Monitoring the kinetics of acetaldehyde using rodent models of alcohol misuse is essential for understanding and managing ethanol\u2010associated diseases. However, quantitation of acetaldehyde in biological specimens after alcohol consumption has been challenging due to its high volatility, relatively low concentrations, and strong reactivity toward biochemical molecules. It was necessary to develop and establish an accurate and high\u2010throughput method to quantitate acetaldehyde and ethanol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gas chromatography\/mass spectrometry in positive chemical ionization mode coupled with a 111\u2010vial headspace autosampler was employed to quantitate acetaldehyde and ethanol using <jats:sup>2<\/jats:sup>H<jats:sub>4<\/jats:sub>\u2010acetaldehyde and <jats:sup>2<\/jats:sup>H<jats:sub>5<\/jats:sub>\u2010ethanol as internal standards. A multidimensional approach was used to develop the method, including sample collection and processing, instrumental data analysis, optimization, and validation. Blood and tissues collected from genetically modified mouse models and their wild\u2010type counterparts were studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The method was validated and applied to quantitate acetaldehyde and ethanol in blood and tissues from multiple mouse studies on ethanol metabolism. Acetaldehyde and ethanol were well\u2010resolved from chromatographic interferences with linear ranges of 6.25\u2013800\u2009\u03bcM for acetaldehyde and 1.25\u2013160\u2009mM for ethanol. Both regression coefficients for calibration curves were &gt;0.999. The within\u2010 and between\u2010run precisions for ethanol in plasma, whole blood, and serum were all &lt;5.0%, and for acetaldehyde in plasma and serum were &lt;9.0%, while in whole blood it was 19.2%. Sample throughput was on the order of 60 samples per 15\u2009h daily, with a maximum of 111 per batch.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Despite some limitations, this validated method proved to be specific, accurate, and reproducible for high\u2010throughput quantitation of acetaldehyde and ethanol in rodent plasma, whole blood, serum, and visceral organs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.70126","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T12:20:33Z","timestamp":1754310033000},"page":"1897-1911","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High\u2010throughput quantitation of acetaldehyde and ethanol in mice using gas chromatography\/mass spectrometry positive chemical ionization"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3458-799X","authenticated-orcid":false,"given":"Yu\u2010Hong","family":"Lin","sequence":"first","affiliation":[{"name":"Laboratory of Liver Diseases NIAAA\/NIH  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases NIAAA\/NIH  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoupeng","family":"Wei","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Neuroscience NIAAA\/NIH  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6002-9986","authenticated-orcid":false,"given":"Guillot","family":"Adrien","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases NIAAA\/NIH  Bethesda Maryland USA"},{"name":"Department of Hepatology &amp; 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