Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients.
Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the catabolism of 5-fluorouracil (5-FU). We measured DPD activity in lymphocytes from 57 consecutive head and neck cancer patients while simultaneously monitoring 5-FU pharmacokinetics during 5-day, continuous infusion (1000 mg/m2/day) 5-FU therapy (82 cycles in total). The mean value for DPD activity was 0.186 +/- 0.068 (SD) nmol/min/mg of protein (range, 0.058 to 0.357). The mean value for 5-FU clearance was 2522.6 +/- 684.2 ml/min/m2 (range, 1052 to 4029). A significant linear correlation was observed between DPD activity and 5-FU clearance (r = 0.716, P less than 0.0001). DPD activity was poorly correlated to plasma uracil concentrations (r = -0.260, P = 0.0215). Likewise, plasma uracil concentrations were poorly correlated to 5-FU clearance (r = -0.214, P = 0.0595). In patients evaluated for more than one cycle (n = 18), there was large intrapatient variability in both DPD activity and 5-FU clearance. No significant difference was noted between cycles for DPD activity or 5-FU clearance (Kruskal-Wallis test). Monitoring DPD activity in lymphocytes may be useful in identifying patients at risk for altered 5-FU disposition.
Fleming
R A
RA
Centre Antoine Lacassagne, Nice, France.
Milano
G
G
Thyss
A
A
Etienne
M C
MC
Renée
N
N
Schneider
M
M
Demard
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000097:blood*; D014498:Uracil / Q000097:blood
D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil