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Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg\/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPAR\u03b1). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081031","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:48:31Z","timestamp":1787219311000},"page":"1031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Moxifloxacin-Mediated Downregulation of Intestinal P-Glycoprotein Alters the Pharmacokinetics of Dabigatran Etexilate: Mechanistic Insights in Rats and PBPK Model-Informed Dose Optimization"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-3147","authenticated-orcid":false,"given":"Yuchen","family":"Qu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"},{"name":"College of Pharmaceutical Science, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"},{"name":"College of Pharmaceutical Science, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yani","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"},{"name":"College of Pharmaceutical Science, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-3267","authenticated-orcid":false,"given":"Yunli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Suzhou Key Laboratory of Translational Research and Application for Radionuclide Therapy and Nuclear Emergency Drugs, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China"},{"name":"Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control, Suzhou 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/CIR.0000000000001193","article-title":"2023 ACC\/AHA\/ACCP\/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the 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