| AIM: To verify dihydrouracil/uracil ratio (UH2/Ura) is a prospect endogenous marker in directing individual pyrimidine dosage. We compared the circadian variation of UH2/Ura with that of liver dihydropyrimidine dehydrogenase (Liver-DPD) as well as peripheral blood mononuclear cell DPD (PBMC-DPD), and we also investigated the relationships between UH2/Ura and pyrimidine pharmacokinetic parameters, efficacy indexes and toxicity indexes.METHOD: The study is consist of five parts:First, 5-fluorouracil (5-FU, 20 mg/kg/h) was continuously infused toSprague-Dawley rats (n = 12) by tail vein within 8 hours and no drug was infused to the control group (n = 12). Liver and whole blood samples were collected from the test group and the control group animals. Whole blood samples from 6 healthy subjects were also collected at various time of the test day. Enzyme-linked immunoabsorbent assay (ELISA) was used to measure theconcentrations of DPD protein in liver and PBMC. "Cosinor"circadian variation analysis was applied to analyze the patterns of DPD activity. The pattern of DPD variation in liver and that in PBMC were compared. These results provided useful data to verify the consistency of circadian variation between UH2/Ura and DPD activity.Second, reverse transcription-polymerase chain reaction (RT-PCR) was applied to study circadian variation of DPD-mRNA levels in rat liver, rat PBMC and human PBMC. Their circadian patterns of DPD-mRNA levels were analyzedby "Cosinor" analysis, respectively. The correlations between DPD mRNA levels and their correspondent DPD protein activities were analyzed by "Pearson"... |
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