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Circadian Rhythm-varying Plasma Concentration of 5-Fluorouracil during a Five-Day Continuous Venous Infusion at a Constant Rate in Cancer Patients¹

Centre Antoine Lacassagne, 06000 Nice [E. P., G. M., A. T., M. S.]; UA CNRS 581 Chronobiologie-Chronopharmacologie, Fondation A. de Rothschild, 75019 Paris [F. L., F. B.]; and Pharmacologie 2, SMST and ICIG (CNRS UA 04-1163), Hôpital Paul-Brousse, 94800 Villejuif [F. L., F. B.], France

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 < 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 < 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 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.

¹ Supported in part by Grant 6180 from ARC, Villejuif, France.

² To whom requests for reprints should be addressed.

Received 10/13/87. Accepted 12/15/87.

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