Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels

In many cancer patients, 5‐fluorouracil (5‐FUra) treatment is toxic and even causes death. Nevertheless, all patients are subjected to a standard therapy regimen because there is no reliable way to identify beforehand those patients who are predisposed to 5‐FUra‐induced toxicity. In this study, we identified the dihydrouracil/uracil (UH2/Ura) ratio in plasma or urine as a potential biomarker reflecting the activity of dihydropyrimidine dehydrogenase (DPD), the rate‐limiting enzyme in 5‐FUra metabolism. UH2/Ura ratios were measured by high‐performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC‐MS/MS) in both healthy subjects ( n =55) and in patients ( n =20) diagnosed with grade I/II gestational trophoblastic tumours. In addition, rats ( n =18) were used as an animal model to verify a correlation between UH2/Ura ratios and DPD levels in the liver. A significant circadian rhythm was observed in UH2/Ura ratios in healthy subjects, whereas a disrupted rhythm occurred in cancer patients who were continuously infused with a high dose of 5‐FUra. In rats, UH2/Ura ratios, liver DPD levels and PBMC DPD levels showed a definite circadian rhythm. Significant linear correlations with liver DPD levels were demonstrated for plasma UH2/Ura ratios ( r =0.883, P <0.01), urine UH2/Ura ratios ( r =0.832, P <0.01) and PBMC DPD levels ( r =0.859, P <0.01). The UH2/Ura ratio in biological fluid was significantly correlated with liver DPD levels; hence, this ratio could be a potential biomarker to identify patients with a deficiency in DPD.British Journal of Pharmacology (2004) 141 , 616–623. doi: 10.1038/sj.bjp.0705651