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This study examines the effects of diet\u2010and\u2010exercise\u2010induced weight loss on key drug\u2010metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3\u20106 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post\u2010weight loss (Phase 2). Twenty\u2010four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, <jats:italic>P<\/jats:italic> &lt;\u00a0.05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2\u2010 or 3\u2010h single plasma sample\u2010based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non\u2010pharmacologically and non\u2010surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.<\/jats:p>","DOI":"10.1002\/jcph.6192","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T10:41:42Z","timestamp":1737542502000},"page":"805-814","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Examining the Impact of Diet\u2010and\u2010Exercise\u2010Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6627-4843","authenticated-orcid":false,"given":"Shuhan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy College of Pharmacy University of Michigan  Ann Arbor MI 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