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Moderate and severe obesity induce complex and dynamic alterations in the gastrointestinal tract, liver and kidneys, which may affect a drug\u2019s pharmacokinetic actions of absorption, distribution, metabolism and excretion. Drug distribution and exposure may also differ based on lipophilicity. Multimorbid patients with obesity and cardiovascular disease are frequently prescribed polypharmacy. Polypharmacy increases the risk of pharmacokinetic-based drug\u2013drug interactions often mediated by the cytochrome P450 enzymes, whose activity can be modified by obesity. Therefore, drug response can be highly and unpredictably variable. New incretin-based therapies can affect the pharmacokinetics of orally co-administered drugs by modifying the gastrointestinal physiology. We review obesity-related pharmacokinetic changes, focusing on common cardiovascular medications. A pragmatic, personalised approach is proposed to reduce variability in response, which may ultimately improve safety and effectiveness.<\/jats:p>","DOI":"10.15420\/ecr.2025.99","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:30:31Z","timestamp":1780050631000},"source":"Crossref","is-referenced-by-count":1,"title":["Obesity and Pharmacokinetic Variability: Implications for Cardiovascular Therapeutics"],"prefix":"10.15420","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6220-686X","authenticated-orcid":false,"given":"Dario","family":"Pitocco","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rg70c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Agostino Gemelli University Polyclinic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Cortelletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-3673","authenticated-orcid":false,"given":"Giovanna","family":"Petrucci","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qvkm315","id-type":"ROR","asserted-by":"publisher"}],"name":"Saint Camillus International University of Health and Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8304-6423","authenticated-orcid":false,"given":"Bianca","family":"Rocca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6096","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"Abernethy DR, Schwartz JB. 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