Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage.
OBJECTIVE
Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU.


METHODS
Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance.


RESULTS
The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25.


CONCLUSIONS
The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.
Gamelin
E
E
Département d'Oncologie Médicale and d'Oncopharmacologie, Centre Paul Papin, Angers, France. cppapin@unimedia.fr
Boisdron-Celle
M
M
Guérin-Meyer
V
V
Delva
R
R
Lortholary
A
A
Genevieve
F
F
Larra
F
F
Ifrah
N
N
Robert
J
J
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016009:Chi-Square Distribution; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood*
D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D002955:Leucovorin; D005472:Fluorouracil