Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase.
1. Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents that are administered concomitantly or sequentially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigated on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enzyme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was determined by measuring the recovery of [14C]5-FU by HPLC. 2. The apparent activity of 5-FU metabolism (2.1-100 microM) showed a linear relationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. Km and Vmax were estimated to be 23 microM and 0.32 nmol min(-1) mg(-1) protein, respectively. Apparent DPD activity for 5-FU (25 microM) in the cytosol from 12 individual donors ranged from 0.017 to 0.39 (0.16 +/- 0.12) nmol min(-1) mg(-1) protein, indicating a large intersubject variance. 3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5-bromouracil (6.3-50 microM), illustrated concentration-dependent inhibition on DPD activity. Isocytosine (6.3-100 microM), used as a negative control, did not affect DPD activity. Bropirimine (6.3-100 microM) also did not show any inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after co-administration of bropirimine with 5-FU prodrugs.
Yamazaki
S
S
Toxicology and Efficacy Research, Tsukuba Research Laboratories, Pharmacia & Upjohn Ltd, Ibaraki, Japan. shinji.yamazaki@am.pnu.com
Hayashi
M
M
Toth
L N
LN
Ozawa
N
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*
D000970:Antineoplastic Agents; D003596:Cytosine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); C033560:bropirimine; D005472:Fluorouracil