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As a result, combination therapy involving antidiabetic drugs and antibiotics has become essential. A newly introduced combination of the antidiabetic drug linagliptin (LIN) and the third-generation cephalosporin antibiotic cefixime (CEF) has been recommended to combat infections in diabetic patients.To optimize therapeutic efficacy and minimize adverse effects associated with this combination therapy, a reliable analytical method was essential for pharmacokinetic analysis and therapeutic drug monitoring. This study present, for the first time, a green high-performance liquid chromatographic method with photodiode array detection (HPLC-PDA) for the simultaneous determination of LIN and CEF in plasma samples. Chromatographic separation was achieved using a Symmetry C\n                    <jats:sub>18<\/jats:sub>\n                    column (250\u00a0mm \u00d7 4.6\u00a0mm, 5\u00a0\u03bcm particle size) under isocratic elution with a mobile phase consisting of 20 mM sodium phosphate (pH 4.3, adjusted with orthophosphoric acid) and methanol (50:50, v\/v). The flow rate was set at 0.8 mLmin\n                    <jats:sup>\u2212\u20091<\/jats:sup>\n                    , with a total run time of 12\u00a0min. The injection volume was 20 \u00b5L and the detection was performed at 230\u00a0nm. The method demonstrated linearity over a range of 50\u20132000 ng mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    for both LIN and CEF, with limits of detection (LOD) of 24 and 21 ngmL\u207b\u00b9 and limits of quantitation (LOQ) of 43 and 45 ngmL\u207b\u00b9 for LIN and CEF, respectively. Validation parameters complied with ICH M10 bioanalytical guidelines. Additionally, the method was successfully applied to a pharmacokinetic study comparing drugs efficacy when administered alone versus concurrently. The results demonstrated that co-administration of LIN and CEF significantly altered their bioavailability: LIN C\n                    <jats:sub>max<\/jats:sub>\n                    increased by 63.2% and AUC increased by 134.2%, while CEF C\n                    <jats:sub>max<\/jats:sub>\n                    decreased by 27.3% and AUC decreased by 23.3%, indicating a bidirectional pharmacokinetic interaction, and underscoring the need for careful monitoring during combination therapy.The greenness of the proposed HPLC-PDA method was evaluated using four metric tools and the findings confirmed the method\u2019s minimal environmental impact. In conclusion, the developed HPLC-PDA method not only provides a reliable tool for therapeutic drug monitoring in clinical practice but also establishes a robust framework for future investigations into drug-drug interactions in human therapeutics.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-57925-0","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T15:05:43Z","timestamp":1783436743000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Green HPLC-PDA method for simultaneous determination of linagliptin and cefixime with pharmacokinetic application in rats"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5821-1968","authenticated-orcid":false,"given":"Weam M.","family":"Othman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehal F.","family":"Farid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nourah Z.","family":"Al-zoman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim A.","family":"Darwish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah S.","family":"Saad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma F.","family":"Abdallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"57925_CR1","doi-asserted-by":"publisher","unstructured":"Kaul, K., Tarr, J. 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