Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients.
A circadian rhythm in the plasma concentration of 5-fluorouracil (5-FUra) is demonstrated in seven patients receiving this drug as a continuous venous infusion at a constant rate for 5 days. All patients had stage C bladder carcinoma and received cis-diamminedichloroplatinum(II) (45-91 mg/m2) on day 1 as a 30-min venous infusion at 5 p.m. Continuous venous infusion of 5-FUra (450-966 mg/m2/day) was started on day 2 at 8:30 a.m. via a volumetric pump and lasted for 5 days (until day 6). Blood samples were obtained on EDTA every 3 h on days 2, 4, and 6 on each patient (20 samples/patient). 5-FUra plasma concentration was determined by high performance liquid chromatography. Data were analyzed by both multiple analysis of variance and cosinor. Mean lowest and highest values (+/- SEM) were, respectively, 254 +/- 33 ng/ml at 1 p.m. and 584 +/- 160 ng/ml at 1 a.m. (F = 2.3; P less than 0.03). Because of large intersubject differences in 24-h mean plasma concentration, data were also expressed as percentages of each patient's 24-h mean. Both analysis of variance and cosinor analysis further validated (P less than 0.0001) a circadian rhythm with a double amplitude (total extent of variation) of 50% of the 24-h mean and an acrophase located at approximately 1 a.m. (estimated time of peak). Such findings warrant a thorough scrutiny at the chronopharmacology of anticancer drugs when designing continuous infusion schedule. A circadian modulation of the infusion rate of this drug may further optimize the therapeutic index of such treatment modality.
Petit
E
E
Centre Antoine Lacassagne, Nice, France.
Milano
G
G
Lévi
F
F
Thyss
A
A
Bailleul
F
F
Schneider
M
M
D000368:Aged; D000704:Analysis of Variance; D002940:Circadian Rhythm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood*; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
D005472:Fluorouracil