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Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.ORCID iD: 0000-0002-0958-3236
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgery, Örnsköldsviks sjukhus, Örnsköldsvik, Sweden.
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2021 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 88, p. 619-631Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The aim was to investigate the pharmacokinetics of preoperatively administered intraperitoneal (IP) 5-FU in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by analyzing levels of 5-FU and target metabolites in peritoneal fluid, plasma, liver, lymph nodes, pancreatic tumour, and pancreatic tissue. These results were correlated to expression of genes encoding enzymes of the 5-FU pathway and cell membrane transporters of 5-FU and FdUMP.

METHODS: Twenty-two patients with PDAC were treated with IP 5-FU before surgery. The postoperative treatment followed a routine clinical protocol. 5-FU and its metabolites were analyzed by LC-MS/MS. The expression of genes encoding enzymes and transporters in the 5-FU pathway was analyzed by qPCR.

RESULTS: After IP treatment, 5-FU could be detected in plasma, lymph nodes, liver, pancreatic tumour, and pancreatic tissue. The highest 5-FU concentration was found in the liver, also expressing high levels of the 5-FU transporter OAT2. 5-FU was converted to active FdUMP in all tissues and the highest concentration was measured in lymph nodes, liver and pancreatic tumour (18.5, 6.1 and 6.7 pmol/g, respectively). There was a correlation between the FdUMP and dUr levels in lymph nodes (r = 0.70, p = 0.0076). In tumours, there was an association between OAT2 expression and FdUMP concentration.

CONCLUSION: The study shows uptake of IP 5-FU and drug metabolism to active FdUMP in pancreatic tumour, liver, and lymph nodes. Extended studies are warranted to evaluate the IP route for 5-FU administration in PDAC patients.

Place, publisher, year, edition, pages
Springer, 2021. Vol. 88, p. 619-631
Keywords [en]
5-Fluorouracil, Gene expression, Intraperitoneal chemotherapy, Pancreatic cancer, Pharmacokinetics
National Category
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-185075DOI: 10.1007/s00280-021-04318-xISI: 000662169200001PubMedID: 34132895Scopus ID: 2-s2.0-85108158762OAI: oai:DiVA.org:umu-185075DiVA, id: diva2:1571725
Funder
Region Västerbotten, 2011-11-11, 2018-03-05, 2019-03-20, RV-216951, RV-764741, RV-864841Available from: 2021-06-23 Created: 2021-06-23 Last updated: 2024-01-25Bibliographically approved

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Öman, MikaelWestermark, SofiaHemmingsson, Oskar

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