Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase

1. Bropirimine (2-amino-5-bromo-6-phenyl-6-pyrimidinone) is a member of a c lass of antineoplastic agents that are administered concomitantly or sequen tially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigat ed on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enz yme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was d etermined by measuring the recovery of [C-14]5-FU by HPLC. 2. The apparent activity of 5-FT metabolism (2.1-100 muM) showed alinear re lationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. K-m and V-max were estimated to be 23 muM and 0.32 nmol min(-1) mg(-1) protein, respecti vely. Apparent DPD activity for 5-FU (25 muM) in the cytosol from 12 indivi dual donors ranged from 0.017 to 0.39 (0.16+/-0.12) nmol min(-1) mg(-1) pro tein, indicating a large intersubject variance. 3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5-bromouracil (6.3-50 muM), illustrated concentration-dependent inhibit ion on DPD activity. Isocytosine (6.3-100 muM), used as a negative control, did not affect DPD activity. Bropirimine (6.3-100 muM) also did not show a ny inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after co-administration of br opirimine with 5-FU prodrugs.