Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action

Background Fluorouracil is widely used for chemotherapy of gastrointestinal cancer; but response rates are poor. Eniluracil is being developed as an inactivator of dihydropyrimidine dehydrogenase, the enzyme that brings about first-pass degradation of fluorouracil. We studied the mechanism of action of eniluracil by measuring with positron emission tomography (PET) the effect of eniluracil on tumour and normal-tissue pharmacokinetics of fluorine-18-labelled fluorouracil. Methods Six patients with advanced gastrointestinal cancers were studied. PET scanning was done after injection of oxygen-15-labelled water to assess tissue blood flow, followed by 1 mg/m(2) F-18-fluorouracil. We compared the pharmacokinetics of F-18-fluorouracil when the patients had not received eniluracil, during a 4-day course of oral eniluracil, and during a 28-day course of oral fluorouracil plus eniluracil. Findings In eniluracil-naive patients, F-18-fluorouracil localised more strongly (mean 0.0234% [SE 0.0019] of injected activity per mL tissue at 11 min) in liver than in tumours (0.0032% [0.0004]). There was substantial inhibition, after eniluracil administration, of radiotracer uptake and retention in normal liver (mean area under the time versus radioactivity curve 0.927 [SE 0.086] vs 1.857 [0.169] m(2) mL(-1) s) and kidneys (1.096 [0.048] vs 5.043 [0.915] m(2) mL(-1) s). There was also an increase in plasma uracil and unmetabolised F-18-fluorouracil and an increase in the radiotracer half-life in tumours (2.3 h to >4.0 h). Interpretation Two events strongly suggested increased exposure of F-18-fluorouracil and its anabolites in the tumours, consistent with the inactivation of dihydropyrimidine dehydrogenase: a selective decrease in radiotracer exposure in normal liver and kidneys compared with tumours; and an increase in radiotracer half-life in tumours.