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A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer.
- Source :
-
Biopharmaceutics & Drug Disposition . Oct2013, Vol. 34 Issue 7, p365-376. 12p. - Publication Year :
- 2013
-
Abstract
- ABSTRACT 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 ( CLtot) and an increased area under the curve ( AUC0-∞) 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 ( r2 = 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, AUC0-∞, CLtot and half-life ( t1/2) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC0-∞, CLtot and t1/2 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01422782
- Volume :
- 34
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Biopharmaceutics & Drug Disposition
- Publication Type :
- Academic Journal
- Accession number :
- 90634030
- Full Text :
- https://doi.org/10.1002/bdd.1851