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To test whether this translates into species-dependent interaction profiles, six flavonoid-profiled citrus peel extracts (Citrus limon, C. depressa Hayata, C. maxima, C. \u00d7 paradisi, C. \u00d7 sinensis, and C. reticulata) were compared in a standardized acute rat model spanning drug disposition, CYP3A and transporter systems, hepatic redox status, and in silico analysis. The naringin-dominated C. \u00d7 paradisi produced the most coordinated disruption of CYP3A and transporter pathways, raising plasma simvastatin acid at 1 h by 506% versus the simvastatin-only group, together with the least favorable redox profile. The polymethoxyflavone-rich C. depressa Hayata perturbed disposition mildly yet raised the hepatic GSH\/GSSG ratio by 227%. Hepatic active-metabolite accumulation was therefore uncoupled from redox outcome, indicating that disposition and redox response are separable axes and that grapefruit cannot represent the citrus genus.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c08143","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:01:42Z","timestamp":1789848102000},"page":"30337-30357","source":"Crossref","is-referenced-by-count":0,"title":["Species-Dependent\nCitrus\u2013Simvastatin Interaction\nProfiles in an Acute Rat Model: Integrating Drug Disposition, Hepatic\nRedox, and Complementary Computational Analysis"],"prefix":"10.1021","volume":"74","author":[{"given":"Wan-Ting","family":"Liao","sequence":"first","affiliation":[{"name":"Show Chwan Memorial Hospital , , ,","place":["Changhua, Taiwan, 500"]},{"name":"National Chung Hsing University , , ,","place":["Taichung, Taiwan, 402"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Cheng","family":"Chi","sequence":"additional","affiliation":[{"name":"China Medical University , , ,","place":["Taichung, Taiwan, 40402"]},{"name":"China Medical University , , ,","place":["Taichung, Taiwan, 40402"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chuan","family":"Li","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7194-7555","authenticated-orcid":true,"given":"Mei-Ling","family":"Li","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Tso","family":"Tsai","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Syuan","family":"Su","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-8447","authenticated-orcid":true,"given":"Kuo-Chiang","family":"Hsu","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]},{"name":"Asia University , , 500 Lioufeng Rd. , Wufeng, ,","place":["Taichung, Taiwan, 41354"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-1376","authenticated-orcid":true,"given":"Shang-Ming","family":"Huang","sequence":"additional","affiliation":[{"name":"China Medical University , , No. 100, Sec. 1, Jingmao Rd. , Beitun Dist., ,","place":["Taichung City, Taiwan, 40604"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"issue":"1","key":"2026093009071614100_cit1","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1080\/10942912.2024.2304274","article-title":"Phytochemical\nand Antioxidant Profile of Citrus Peel Extracts in Relation to Different\nExtraction Parameters","volume":"27","author":"Ashraf","year":"2024","journal-title":"Int. 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Agric.\nFood Chem."},{"issue":"7","key":"2026093009071614100_cit28","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1002\/jsfa.3959","article-title":"Antioxidant Properties, Radical Scavenging Activity\nand Biomolecule Protection Capacity of Flavonoid Naringenin and Its\nGlycoside Naringin: A Comparative Study","volume":"90","author":"Cavia-Saiz","year":"2010","journal-title":"J.\nSci. Food Agric."},{"key":"2026093009071614100_cit29","doi-asserted-by":"publisher","first-page":"118411","DOI":"10.1016\/j.molliq.2021.118411","article-title":"Insights into\nMolecular Mechanism\nof Action of Citrus Flavonoids Hesperidin and Naringin on Lipid Bilayers\nUsing Spectroscopic, Calorimetric, Microscopic and Theoretical Studies","volume":"347","author":"Altunayar-Unsalan","year":"2022","journal-title":"J. Mol. 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Nutr."},{"issue":"6","key":"2026093009071614100_cit44","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/clpt.1993.84","article-title":"Grapefruit Juice\u2013Felodipine\nInteraction: Mechanism, Predictability, and Effect of Naringin","volume":"53","author":"Bailey","year":"1993","journal-title":"Clin. Pharmacol. Ther."},{"issue":"1\u20132","key":"2026093009071614100_cit45","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.ejps.2012.02.014","article-title":"Inhibition of Hepatic\nUptake Transporters by Flavonoids","volume":"46","author":"Mandery","year":"2012","journal-title":"Eur. J. Pharm.\nSci."},{"issue":"3","key":"2026093009071614100_cit46","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1124\/jpet.300.3.1036","article-title":"Unmasking the Dynamic\nInterplay Between\nIntestinal P-Glycoprotein and CYP3A4","volume":"300","author":"Cummins","year":"2002","journal-title":"J. Pharmacol.\nExp. 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