{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:44:42Z","timestamp":1774950282183,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Doxorubicin is an anthracycline chemotherapeutic agent widely used in the treatment of breast cancer. However, its clinical utility is limited by the drug\u2019s resistance development, low oral bioavailability, and dose-dependent side effects. The semi-essential amino acid, L-arginine, has gained attention as a potential adjuvant that could improve the drug distribution and cytotoxic effectiveness of chemotherapeutics. This study aimed to explore the multifunctional effect of L-arginine on the intestinal absorption and anti-breast cancer activity of doxorubicin. Methods: The rabbit in situ intestinal perfusion technique was employed to investigate the membrane transport parameters of doxorubicin both in the absence and presence of L-arginine. Furthermore, the effect of L-arginine on the cytotoxic activity of doxorubicin against breast cancer cells (MCF-7) was assessed using the MTT assay. Results: Co-perfusion of L-arginine with doxorubicin enhanced the fraction of doxorubicin absorbed, with a recorded 4.3-fold enhancement in the jejuno-ileum and a 1.5-fold enhancement in the colon segment. In MCF-7 cells, co-treatment with L-arginine resulted in a significant potentiation of doxorubicin cytotoxicity. At L-arginine concentrations of 10 \u03bcM and 50 \u03bcM, the recorded IC50 decreased from 41.3 \u03bcM to 8.2 \u03bcM and to 22.1 \u03bcM, respectively. The superior efficacy of 10 \u03bcM L-arginine compared to 50 \u03bcM reflected a biphasic concentration-dependent response. Conclusions: L-arginine modulated two critical aspects of doxorubicin efficacy, intestinal absorption and cytotoxic activity. The biphasic response emphasizes the importance of L-arginine dose optimization. These findings support the potential of L-arginine as a safe adjuvant for developing oral doxorubicin formulations. This approach can reduce the dose-related toxicity of doxorubicin and improve therapeutic outcomes.<\/jats:p>","DOI":"10.3390\/ph19040546","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["L-Arginine as an Adjuvant Chemosensitizer: Enhancement of Intestinal Permeability and Cytotoxic Activity of Doxorubicin"],"prefix":"10.3390","volume":"19","author":[{"given":"Ghada","family":"Saad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology, College of Pharmacy, Horus University, New Damietta 34517, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rana M.","family":"Alquwayi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9943-4927","authenticated-orcid":false,"given":"Hanin B.","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah B.","family":"Aldahmashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5908-8402","authenticated-orcid":false,"given":"Aryam M.","family":"Alahmary","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7073-3975","authenticated-orcid":false,"given":"Shouq K.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima R.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghadah T.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afnan J.","family":"Alrashidi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norah K.","family":"Aldousari","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haifa F.","family":"Alsubiei","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lama H.","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meaad H.","family":"Aldossary","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8443-7351","authenticated-orcid":false,"given":"Amal A.","family":"Sultan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 39911, Saudi Arabia"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/joim.12084","article-title":"Breast cancer as a systemic disease: A view of metastasis","volume":"274","author":"Redig","year":"2013","journal-title":"J. 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