title: Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer.
abstract: Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[(18)F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K(I) = 0.0033 +/- 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K(I) = 0.7313 +/- 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66-91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94-98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.
authors: Cancer Research Campaign Positron Emission Tomography Oncology Group, Department of Cancer Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. eric.aboagye@ic.ac.uk
authors: E O
authors: EO
authors: Aboagye
authors: A
authors: A
authors: Saleem
authors: V J
authors: VJ
authors: Cunningham
authors: S
authors: S
authors: Osman
authors: P M
authors: PM
authors: Price
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D042943:Dihydrouracil Dehydrogenase (NADP); D004791:Enzyme Inhibitors / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D005472:Fluorouracil / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D008954:Models, Biological; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism; D014055:Tomography, Emission-Computed; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil