title: Pre-therapeutic assessment of plasma dihydrouracil/uracil ratio for predicting the pharmacokinetic parameters of 5-fluorouracil and tumor growth in a rat model of colorectal cancer.
abstract: We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r(2)=0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan. ky05122@poppy.kyoto-phu.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Kae
authors.initials: K
authors.lastname: Okada
authors.forename: Kazuki
authors.initials: K
authors.lastname: Imoto
authors.forename: Shota
authors.initials: S
authors.lastname: Kuwano
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D047368:Tumor Burden / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood*
chemical_list: D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil