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

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Abstract
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, Pr=0.832, Pr=0.859, PBritish Journal of Pharmacology (2004) 141, 616–623. doi:10.1038/sj.bjp.0705651