title: Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study.
abstract: OBJECTIVE
  Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis.
  
  
  METHODS
  In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days.
  
  
  RESULTS
  For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime.
  
  
  CONCLUSIONS
  Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Room HE-118, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. i.konings@erasmusmc.nl
authors.forename: Inge R H M
authors.initials: IR
authors.lastname: Konings
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.forename: Inge M
authors.initials: IM
authors.lastname: Ghobadi Moghaddam-Helmantel
authors.forename: Linda M
authors.initials: LM
authors.lastname: van Dam
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018277:Carcinoma, Mucoepidermoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017551:Microdialysis; D008875:Middle Aged; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil