{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:44:08Z","timestamp":1771548248231,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine\u2019s activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus\u2122, predicting the PK parameters and plasma concentration\u2013time profiles. The integrative biomedical data analyses presented here are promising, with some regimens of oral administration reaching higher AUC in comparison to the traditional IV infusion, supporting this route of administration as a viable alternative to IV infusions. This study further contributes to personalized health care based on potential new formulations for oral administration of gemcitabine, as well nanotechnology-based drug delivery systems.<\/jats:p>","DOI":"10.3390\/cimb43030153","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T20:23:21Z","timestamp":1638908601000},"page":"2189-2198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration"],"prefix":"10.3390","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3271-6444","authenticated-orcid":false,"given":"Abigail","family":"Ferreira","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"LAQV\/REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Rui","family":"Lapa","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/03602530902741828","article-title":"Clinical pharmacology and pharmacogenetics of gemcitabine","volume":"41","author":"Wong","year":"2009","journal-title":"Drug Metab. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"v7","DOI":"10.1093\/annonc\/mdj941","article-title":"Cellular pharmacology of gemcitabine","volume":"17","author":"Mini","year":"2006","journal-title":"Ann. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"475","DOI":"10.2147\/DDDT.S156766","article-title":"Combination therapy versus gemcitabine monotherapy in the treatment of elderly pancreatic cancer: A meta-analysis of randomized controlled trials","volume":"12","author":"Jin","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.ejca.2012.08.019","article-title":"Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: A meta-analysis of randomised trials","volume":"49","author":"Ciliberto","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1200\/JCO.2005.06.023","article-title":"Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial","volume":"23","author":"Louvet","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_7","unstructured":"USA Food and Drug Admistration (2021, April 10). GEMZAR\u00ae (Gemcitabine HCl) for Injection. FDA Label, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/020509s069lbl.pdf."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1007\/s00280-013-2165-2","article-title":"Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors","volume":"71","author":"Yamamoto","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00280-012-2017-5","article-title":"In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation","volume":"71","author":"Hao","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3390\/pharmaceutics5020261","article-title":"Preclinical absorption, distribution, metabolism, and excretion of an oral amide prodrug of gemcitabine designed to deliver prolonged systemic exposure","volume":"5","author":"Wickremsinhe","year":"2013","journal-title":"Pharmaceutics"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ferreira, A., Lapa, R., and Vale, N. (2019). Combination of Gemcitabine with Cell-Penetrating Peptides: A Pharmacokinetic Approach Using in Silico Tools. Biomolecules, 9.","DOI":"10.3390\/biom9110693"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1039\/C9MD00489K","article-title":"Development of potent CPP6-gemcitabine conjugates against human prostate cancer cell line (PC-3)","volume":"11","author":"Correia","year":"2020","journal-title":"RSC Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1016\/j.bmcl.2017.04.086","article-title":"Gemcitabine anti-proliferative activity significantly enhanced upon conjugation with cell-penetrating peptides","volume":"27","author":"Vale","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","unstructured":"Food and Drug Administration (2000). Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry, Food and Drug Administration, Center for Drug Evaluation and Research, Department of Health and Human Services."},{"key":"ref_15","unstructured":"(2021, April 10). BioRender\u2122. Available online: https:\/\/app.biorender.com\/."},{"key":"ref_16","unstructured":"DrugBank (2021, April 10). Gemcitabine on DrugBank Database. Available online: https:\/\/www.drugbank.ca\/drugs\/DB00441."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_18","first-page":"2307","article-title":"Preparation and evaluation of polymeric microparticulates for improving cellular uptake of gemcitabine","volume":"7","author":"Lim","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1631\/jzus.2007.B0307","article-title":"Comparison of pharmacokinetics, efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer","volume":"8","author":"Wang","year":"2007","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.bbmt.2007.07.008","article-title":"Phase I and pharmacokinetic study of gemcitabine administered at fixed-dose rate, combined with docetaxel\/melphalan\/carboplatin, with autologous hematopoietic progenitor-cell support, in patients with advanced refractory tumors","volume":"13","author":"Nieto","year":"2007","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1093\/annonc\/mdf219","article-title":"Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma","volume":"13","author":"Faivre","year":"2002","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1124\/dmd.119.089334","article-title":"Intracellular Cytidine Deaminase Regulates Gemcitabine Metabolism in Pancreatic Cancer Cell Lines","volume":"48","author":"Jordheim","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/s41416-018-0307-3","article-title":"Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine\/platinum-treated advanced non-small-cell lung cancer: A prospective validation study","volume":"119","author":"Tibaldi","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bcp.2019.06.013","article-title":"Mechanisms of gemcitabine oral absorption as determined by in situ intestinal perfusions in mice","volume":"168","author":"Thompson","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","first-page":"1003","article-title":"Intestinal nucleoside transporters: Function, expression, and regulation","volume":"8","author":"Urtasun","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1158\/1078-0432.CCR-07-4521","article-title":"Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study","volume":"14","author":"Veltkamp","year":"2008","journal-title":"Clin. Cancer Res."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/43\/3\/153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:42:35Z","timestamp":1760168555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/43\/3\/153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,7]]},"references-count":26,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cimb43030153"],"URL":"https:\/\/doi.org\/10.3390\/cimb43030153","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,7]]}}}