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P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug\u2013drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including in silico, in vitro, ex vivo, and in vivo methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.<\/jats:p>","DOI":"10.3390\/molecules28227532","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:46:47Z","timestamp":1699843607000},"page":"7532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Study Models of Drug\u2013Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5684-7214","authenticated-orcid":false,"given":"J\u00e9ssica","family":"Veiga-Matos","sequence":"first","affiliation":[{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Toxicology Unit (Universidad de Salamanca), Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6836-6138","authenticated-orcid":false,"given":"Ana I.","family":"Morales","sequence":"additional","affiliation":[{"name":"Toxicology Unit (Universidad de Salamanca), Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2540-4461","authenticated-orcid":false,"given":"Marta","family":"Prieto","sequence":"additional","affiliation":[{"name":"Toxicology Unit (Universidad de Salamanca), Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7548","authenticated-orcid":false,"given":"Renata","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrd3028","article-title":"Membrane Transporters in Drug Development","volume":"9","author":"Giacomini","year":"2010","journal-title":"Nat. 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