Premium
Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity
Author(s) -
Kobuchi Shinji,
Akutagawa Mako,
Ito Yukako,
Sakaeda Toshiyuki
Publication year - 2019
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2168
Subject(s) - capecitabine , dihydropyrimidine dehydrogenase , uracil , pharmacokinetics , fluorouracil , medicine , pharmacology , plasma levels , chemistry , endocrinology , cancer , colorectal cancer , biochemistry , thymidylate synthase , dna
Capecitabine is a 5‐fluorouracil (5‐FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH 2 ) 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 UH 2 /Ura ratio is still unknown. This study evaluated the time‐course alterations of the plasma UH 2 /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 UH 2 /Ura ratio temporarily increases following administration of capecitabine, possibly related to the DPD activity levels. The plasma UH 2 /Ura ratio might assist in monitoring the alteration of DPD activity levels in capecitabine treatments.