954 Circadian variation of dihydropyrimidine dehydrogenase (DPD), uridine phosphorylase (UP), β-alanine ( β-ALA) and 5-fluorouracil, (5-FU) during continuous infusion (CI) fluoropyrimidines (FP)

Abstract

There is evidence for a circadian variation of the major pyrimidine catabolic enzyme DPD. We studied the relationship between plasma levels of DPD, the anabolic enzyme UP, the Uracil catabolite β-ALA and 5-FU during CI of FP. Methods So far 8 patients (pts) who were treated with CI of 5-FU 300–450 mg/m2/day or FUDR (floxuridine) 0.175–0.325 mg/kg/day for 14 days every 4 weeks entered the study. Blood samples for the determination of plasma levels of DPD, UP, β-ALA and 5-FU were taken 7 times every 4 hours on day 7 and 14 of one chemotherapy course. The amount of β-ALA was quantified by HPLC separation with postcolumn o-phtaldehyde detection. DPD and UP activities were determined in purified leucocytes with radiochemical assays. 5-FU levels were measured by GC-MS. Results For pts analyzed up to date a circadian rhythm was observed for the activities of DPD and UP and maximal activities were observed between 12 AM and 4 PM. A profound circadian variation was also observed for the β-ALA concentrations with peak values occurring between 4 PM and 8 PM. An inverse pattern was observed for the levels of 5-FU compared to that of β-ALA. Conclusion We observed not only a circadian variation of the levels of DPD and 5-FU, but also for β-ALA and UP. Surprisingly DPD and UP demonstrated the same pattern. There is evidence for a circadian variation of the major pyrimidine catabolic enzyme DPD. We studied the relationship between plasma levels of DPD, the anabolic enzyme UP, the Uracil catabolite β-ALA and 5-FU during CI of FP. So far 8 patients (pts) who were treated with CI of 5-FU 300–450 mg/m2/day or FUDR (floxuridine) 0.175–0.325 mg/kg/day for 14 days every 4 weeks entered the study. Blood samples for the determination of plasma levels of DPD, UP, β-ALA and 5-FU were taken 7 times every 4 hours on day 7 and 14 of one chemotherapy course. The amount of β-ALA was quantified by HPLC separation with postcolumn o-phtaldehyde detection. DPD and UP activities were determined in purified leucocytes with radiochemical assays. 5-FU levels were measured by GC-MS. For pts analyzed up to date a circadian rhythm was observed for the activities of DPD and UP and maximal activities were observed between 12 AM and 4 PM. A profound circadian variation was also observed for the β-ALA concentrations with peak values occurring between 4 PM and 8 PM. An inverse pattern was observed for the levels of 5-FU compared to that of β-ALA. We observed not only a circadian variation of the levels of DPD and 5-FU, but also for β-ALA and UP. Surprisingly DPD and UP demonstrated the same pattern.