{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:39:35Z","timestamp":1785523175920,"version":"3.56.0"},"reference-count":74,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bariatric surgery involves major changes in the anatomy and physiology of the gastrointestinal tract, which may alter oral drug bioavailability and efficacy. Phosphodiesterase-5 inhibitor (PDE5i) drugs are the first-line treatment of erectile dysfunction, a condition associated with a higher BMI. In this paper, we examine the PDE5i vardenafil for possible post-bariatric changes in solubility\/dissolution and absorption. Vardenafil solubility was determined in vitro, as well as ex vivo using aspirated gastric contents from patients prior to vs. following bariatric procedures. Dissolution was tested in vitro under unoperated stomach vs. post-gastric sleeve\/bypass conditions. Lastly, the gathered solubility\/dissolution data were used to produce an in silico physiologically based pharmacokinetic (PBPK) model (GastroPlus\u00ae), where gastric volume, pH, and transit time, as well as proximal GI bypass (when relevant) were all adjusted for, evaluating vardenafil dissolution, gastrointestinal compartmental absorption, and pharmacokinetics before vs. after different bariatric procedures. pH-dependent solubility was demonstrated for vardenafil with low (pH 7) vs. high solubility (pH 1\u20135), which was confirmed ex vivo. The impaired dissolution of all vardenafil doses under post-gastric bypass conditions was demonstrated, contrary to complete (100%) dissolution under pre-surgery and post-sleeve gastrectomy conditions. Compared to unoperated individuals, PBPK simulations revealed altered pharmacokinetics post-gastric bypass (but not after sleeve gastrectomy), with 30% lower peak plasma concentration (Cmax) and 40% longer time to Cmax (Tmax). Complete absorption after gastric bypass is predicted for vardenafil, which is attributable to significant absorption from the large intestine. The biopharmaceutics and PBPK analysis indicate that vardenafil may be similarly effective after sleeve gastrectomy as before the procedure. However, results after gastric bypass question the effectiveness of this PDE5i. Specifically, vardenafil\u2019s onset of action might be delayed and unpredictable, negatively affecting the practicality of the intended use.<\/jats:p>","DOI":"10.3390\/biom15070975","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T11:19:27Z","timestamp":1751887167000},"page":"975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Physiologically Based Pharmacokinetic Modeling for Predicting Drug Levels After Bariatric Surgery: Vardenafil Exposure Before vs. After Gastric Sleeve\/Bypass"],"prefix":"10.3390","volume":"15","author":[{"given":"Daniel","family":"Porat","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5995-4237","authenticated-orcid":false,"given":"Oleg","family":"Dukhno","sequence":"additional","affiliation":[{"name":"Department of Surgery B, Soroka University Medical Center, Beer-Sheva 8410101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8291-791X","authenticated-orcid":false,"given":"Sandra","family":"Cviji\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-3514","authenticated-orcid":false,"given":"Arik","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410101, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e232145","DOI":"10.1001\/jamanetworkopen.2023.2145","article-title":"Trends in the Prevalence of Metabolically Healthy Obesity Among US Adults, 1999\u20132018","volume":"6","author":"Wang","year":"2023","journal-title":"JAMA Netw. 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