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We present a high-throughput (HT) ambient mass spectrometry (MS) approach using desorption electrospray ionization (DESI) that unites three complementary capabilities available using two different mass spectrometers: (A) untargeted screening to survey the metabolic space, (B) product ion scan tandem MS to characterize novel metabolites, and (C) multiple reaction monitoring (MRM) to deliver precise quantitation of substrates and metabolites. Applying the methodology to diverse in vitro systems, we track substrate depletion, metabolite formation, and DDIs with quantitative accuracy (error &amp;lt;9% for MRM quantitation) validated against liquid chromatography (LC) MS. The method operates two to three orders of magnitude faster (1 s\/sample) than traditional LC\u2013MS methods. This allows hundreds of substrate\u2013enzyme\u2013DDI combinations to be followed in time-resolved fashion using \u223c4 \u00d7 104 individual DESI-MS measurements, acquired at a rate of &amp;gt;3,000 measurements\/hour. By combining HT screening and targeted monitoring, the DESI-MS approach delivers metabolic discovery with robust quantitation, overcoming a central bottleneck in large-scale drug metabolism studies. This investigation aims to provide a high-throughput analytical approach with broad utility in drug discovery, toxicology, and precision medicine workflows.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c04039","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:02:05Z","timestamp":1790161325000},"page":"29604-29615","source":"Crossref","is-referenced-by-count":0,"title":["Drug Metabolism\nand Drug\u2013Drug Interactions\nStudied Using High-Throughput Ambient Mass Spectrometry"],"prefix":"10.1021","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9174-0105","authenticated-orcid":true,"given":"Mousumi","family":"Saha","sequence":"first","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0701-4347","authenticated-orcid":true,"given":"Nari","family":"Talaty","sequence":"additional","affiliation":[{"name":"Abbvie Development Sciences , , ,","place":["North Chicago, Illinois, United States, 60064"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0218-407X","authenticated-orcid":true,"given":"Nicola\u0301s M.","family":"Morato","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdiyeh","family":"Shahi","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8899-4470","authenticated-orcid":true,"given":"Christopher J.","family":"Welch","sequence":"additional","affiliation":[{"name":"Indiana Consortium for Analytical Science and Engineering (ICASE) , , ,","place":["Indianapolis, Indiana, United States, 46202"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Feng","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3988-6454","authenticated-orcid":true,"given":"Christina R.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47904"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wagner","sequence":"additional","affiliation":[{"name":"Abbvie Development Sciences , , ,","place":["North Chicago, Illinois, United States, 60064"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kaerner","sequence":"additional","affiliation":[{"name":"Eli Lilly & Co , , ,","place":["Louisville, Colorado, United States, 80027"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-9603","authenticated-orcid":true,"given":"Robert Graham","family":"Cooks","sequence":"additional","affiliation":[{"name":"Purdue University , , , ,","place":["West Lafayette, Indiana, United States, 47907"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"9237","key":"2026102006570880100_cit1","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1016\/S0140-6736(00)02799-9","article-title":"Adverse Drug Reactions: Definitions, Diagnosis, and\nManagement","volume":"356","author":"Edwards","year":"2000","journal-title":"Lancet"},{"issue":"6","key":"2026102006570880100_cit2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/S1474-4422(03)00409-5","article-title":"Clinically Important\nDrug Interactions in Epilepsy:\nGeneral Features and Interactions between Antiepileptic Drugs","volume":"2","author":"Patsalos","year":"2003","journal-title":"Lancet Neurol."},{"issue":"5","key":"2026102006570880100_cit3","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1038\/nrd1720","article-title":"Elucidating Mechanisms of Drug-Induced\nToxicity","volume":"4","author":"Liebler","year":"2005","journal-title":"Nat. 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