Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kirurgi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Surgery (hsv//eng)

Nyckelord

5-Fluorouracil

Intraperitoneal chemotherapy

Pancreatic cancer

Pharmacokinetics

Gene expression

organic anion transporter-2

phase-i

5-fluorouracil

multicenter

gemcitabine

inhibition

resistance

chemotherapy

vasopressin

modulation

Oncology

Pharmacology & Pharmacy

5-Fluorouracil

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)