Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity

Abstract

Capecitabine is a 5‐fluorouracil (5‐FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH2) to uracil (Ura) is expected to gain relevance as an indirect‐response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate‐limiting enzyme in the catabolism of 5‐FU in the capecitabine‐based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH2/Ura ratio is still unknown. This study evaluated the time‐course alterations of the plasma UH2/Ura ratio in rats treated with 180 mg/kg capecitabine. The molar ratio tended to increase within 1.5 h (1.85 ± 0.76 at 1.5 h after administration of capecitabine) and gradually recovered to its initial level (1.00 ± 0.46). The results of the current study suggest that the plasma UH2/Ura ratio temporarily increases following administration of capecitabine, possibly related to the DPD activity levels. The plasma UH2/Ura ratio might assist in monitoring the alteration of DPD activity levels in capecitabine treatments.

Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics

“…Thymine and cytosine are the pyrimidine bases that constitute DNA and participate in the metabolism of pyrimidine nucleotides. Dihydrouracil can be converted into uracil by dihydropyrimidine dehydrogenase, and the ratio of the two chemical components can be used to examine the enzyme activity of the dihydropyrimidine dehydrogenase [47].…”