Blocking catabolism with eniluracil enhances PET studies of 5-[F-18]fluorouracil pharmacokinetics

Noninvasive methods for measuring the pharmacokinetics of chemotherapeutic drugs such as 5-fluorouracil (FU) are needed for individualized optimizatio n of treatment regimens. PET imaging of [F-18]FU (PET/[F-18]FU) is potentia lly useful in this context, but PET/[F-18]FU is severely hampered by low tu mor uptake of radiolabel and rapid catabolism of FU in vivo. Pretreatment w ith eniluracil (5-ethynyluracil) prevents catabolism of FU. Hypothesizing t hat suppression of catabolism would enhance PET/[F-18]FU, we examined the e ffects of eniluracil on the short-term pharmacokinetics of the radiotracer. Methods: Anesthetized rats bearing a subcutaneous rat colorectal tumor wer e given eniluracil or placebo and injected intravenously 1 h later with [F- 18]FU Or [H-3]FU. In the F-18 studies, dynamic PET image sequences were obt ained 0-2 h after injection. Tumors were excised and frozen at 2 h and then analyzed for labeled metabolites by high-performance liquid chromatography . Biodistribution of radiolabel was determined by direct tissue assay. Resu lts: Eniluracil improved tumor visualization in PET images. With eniluracil , tumor standardized uptake values ([activity/g]/[injected activity/g body weight]) increased from 0.72 +/- 0.06 (mean +/- SEM; n = 6) to 1.57 +/- 0.2 0 (n = 12; P < 0.07), and tumor uptake increased by factors of 2 or more re lative to plasma (P < 0.05) and bone, liver, and kidney (P < 0.01), Without eniluracil (n = 5), 57% +/- 4% of recovered radiolabel in tumor at 2 h was on catabolites, with the rest divided among FU (2% +/- 1%), anabolites of FU (38% +/- 7%), and unidentified peaks (4% +/- 2%). With eniluracil (n = 8 ), catabolites, FU, and anabolites comprised 2% +/- 1%, 41% +/- 5%, and 57% +/- 4%, respectively, of the recovered radiolabel in tumors, Conclusion: E niluracil increased tumor accumulation of F-18 relative to host tissues and fundamentally changed the biochemical significance of that accumulation. W ith catabolism suppressed, tumor radioactivity reflected the therapeuticall y relevant aspect of FU pharmacokinetics-namely, uptake and anabolic activa tion of the drug. With this approach, it may be feasible to measure the tra nsport and anabolism of [F-18]FU in tumors by kinetic modeling and PET. Suc h information may be useful in predicting and increasing tumor response to FU.