Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion.

作者：Barry Harris, R Song, Seng-Jaw Soong, Robert B. Diasio · 发表于：PubMed · 年份：1990 · 被引用次数：445 · 研究领域：Colorectal Cancer Treatments and Studies、Colorectal Cancer Screening and Detection、Gastric Cancer Management and Outcomes

The activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells and plasma concentration of 5-fluorouracil (FUra) were simultaneously determined in cancer patients receiving FUra by protracted continuous infusion (300 mg/m2/day). Blood samples were drawn every 3 h over 24-h period and the resulting DPD and FUra values analyzed for circadian periodicity. In the seven patients studied, a circadian rhythm of DPD activity was observed (P less than 0.00001, Cosinor analysis) with the peak of activity at 1 a.m. (0.197 +/- 0.007 nmol/min/mg) and the trough at a 1 p.m. (0.113 +/- 0.007 nmol/min/mg). In addition, a circadian rhythm was observed for the plasma concentrations of FUra obtained over a 24-h period (P less than 0.00001, Cosinor analysis) with peak values (27.4 +/- 1.3 ng/ml) occurring at 11 a.m. and trough values (5.6 +/- 1.3 ng/ml) occurring at 11 p.m. The ratio of the maximum concentration of FUra to the minimum concentration observed was almost 5-fold. This study demonstrates a circadian variation of DPD activity in human peripheral blood mononuclear cells and a circadian variation of FUra plasma levels in patients receiving FUra by protracted continuous infusion. An inverse relationship between the circadian patterns of DPD activity and FUra plasma levels was also noted, suggesting that an association may exist between DPD activity and FUra plasma concentration. Further evidence of an association between DPD activity in peripheral blood monon...