title: A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer.
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 (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, 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.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.forename: Shota
authors.initials: S
authors.lastname: Kuwano
authors.forename: Kazuki
authors.initials: K
authors.lastname: Imoto
authors.forename: Kae
authors.initials: K
authors.lastname: Okada
authors.forename: Asako
authors.initials: A
authors.lastname: Nishimura
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014498:Uracil / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: anti-cancer agent; biomarker; dihydropyrimidine dehydrogenase; pharmacokinetics