Purpose: The activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in fluorouracil catabolism, has been reported to vary according to time of day. We wished to determine whether peak and trough DPD activities occurred at uniform times in six subjects, whether individual patterns fit a discernible profile, and whether such patterns were consistent and reproducible over time.
Methods: Mononuclear cells were isolated from peripheral blood at 3-h intervals over a 24-h period on three different dates over a 6-month period. DPD activity was determined by incubating cellular lysates with [3H]FUra and measuring [3H]dihydrofluorouracil formation over time.
Results: When the data were averaged by study date for each subject, the median value for the average DPD activity (11.0 pmol/min per 10(6) cells) was significantly different from both the median peak (21.1 pmol/min per 10(6) cells, P = 0.004) and median trough activities (4.0 pmol/min per 10(6) cells, P = 0.002). Within the six subjects, the average DPD activity for the three study dates differed by a median of 2.4-fold (range 1.2- to 4.8-fold). The time at which peak and trough DPD activities occurred varied between subjects: 8 of the 17 peaks (47%) occurred between 10:00 p.m. and 6:00 a.m., 6 (35%) occurred between 8:00 a.m. and 3:00 p.m., and 3 (18%) occurred between 5:00 p.m. and 8:15 p.m. Thus, the time of day when the peak occurred was essentially randomly distributed over the 24-h period of observation (P = 0.68). Ten (59%) of the trough DPD activities occurred between 7:00 a.m. and 3:00 p.m. The median interval between the peak and trough was 6.5 h. The data were also expressed as percent of the mean for each individual's 24-h sampling period, and reordered as time from peak rather than as the actual time of day. When the combined data for all cycles was considered, the trough occurred 6-9 h after the peak, and the DPD levels subsequent to the peak did not display merely random variation (P = 0.0055).
Conclusions: DPD activity levels and the times at which peak and trough DPD activities occurred varied both between and within subjects. If fluctuations in DPD activity influence the tolerability of fixed-rate infusions of FUra, these data suggest that a single variable-rate infusion regimen may not be suitable for all patients nor for a given individual treated over several months.