title: Pharmacokinetic/pharmacodynamic modeling of 5-fluorouracil by using a biomarker to predict tumor growth in a rat model of colorectal cancer.
abstract: We developed a pharmacokinetic/pharmacodynamic (PK/PD) model with the value of the plasma ratio of dihydrouracil (UH2)/uracil (Ura), which is a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase activity, determined before 5-fluorouracil (5-FU) treatment to simulate the growth of tumors after 5-FU treatment in rats with colorectal cancer (CRC). In the PK/PD model, the value of the elimination rate constant of 5-FU-ke -was estimated using the plasma UH2/Ura ratio observed before 5-FU treatment for simulating PKs of 5-FU and tumor growth. The PK/PD model with plasma UH2/Ura ratio effectively captured the features of tumor growth and the anticancer effect of 5-FU treatment, which provided reliable parameter estimates. In addition to an appropriate dosing regimen, pretherapeutic assessment of the UH2/Ura ratio in the plasma of CRC patients and PK/PD analysis with the plasma UH2/Ura ratio could enable the development of an optimal therapeutic scheme for each patient.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: ky05122@poppy.kyoto-phu.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Imoto
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Kuwano
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D003106:Colon / Q000187:drug effects / Q000473:pathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005472:Fluorouracil / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000187:drug effects / Q000473:pathology; 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