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A predictive biomarker for altered 5‐fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer
Author(s) -
Kobuchi Shinji,
Kuwano Shota,
Imoto Kazuki,
Okada Kae,
Nishimura Asako,
Ito Yukako,
Shibata Nobuhito,
Takada Kanji
Publication year - 2013
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.1851
Subject(s) - pharmacokinetics , medicine , colorectal cancer , fluorouracil , endocrinology , biomarker , bolus (digestion) , uracil , chemistry , pharmacology , cancer , biochemistry , dna
The relationship between the plasma ratio of dihydrouracil/uracil (UH2/Ura) and hepatic dihydropyrimidine dehydrogenase (DPD) activity after repeated 5‐fluorouracil (5‐FU) treatment in rats with colorectal cancer (CRC) was investigated. Repeated intravenous 5‐FU bolus injections resulted in a significant decrease in the total clearance ( CL tot ) and an increased area under the curve ( AUC 0‐∞ ) in CRC rats. Furthermore, the hepatic DPD levels and the plasma ratio of UH2/Ura decreased significantly and lost their circadian rhythms in CRC rats treated repeatedly with 5‐FU, although significant circadian variation in the two parameters was observed in the control CRC rats. Moreover, a significant correlation was found between the plasma ratio of UH2/Ura and hepatic DPD activity in CRC rats untreated and treated with single or repeated 5‐FU administration ( r 2 = 0.865, p < 0.01). The ratio of UH2/Ura in plasma could be a predictive biomarker of the suppression of hepatic DPD levels during repeated 5‐FU‐based treatment. Furthermore, by plotting the observed pharmacokinetic parameters of 5‐FU against hepatic DPD activity levels predicted by the ratio of UH2/Ura in plasma, AUC 0‐∞ , CL tot and half‐life ( t 1/2 ) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC 0‐∞ , CL tot and t 1/2 of 5‐FU after single or repeated administration of 5‐FU is the hepatic DPD activity and it could be assessed by the ratio of UH2/Ura in plasma. Copyright © 2013 John Wiley & Sons, Ltd.