title: Drug delivery of oral anti-cancer fluoropyrimidine agents.
abstract: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Koh
authors.identifier: 0000-0001-7303-9430
authors.initials: K
authors.lastname: Miura
authors.affiliation: b Division of Cancer Chemotherapy , Miyagi Cancer Center Research Institute , Natori , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.affiliation: c Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Investigational Drug Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: d Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Regulatory Affairs Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Rhie
authors.affiliation: e Miyagi Cancer Center Research Institute , Division of Cancer Stem Cell , Natori , Japan.
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.affiliation: f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kakugawa
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Satoh
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinouchi
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kawai
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kanazawa
authors.affiliation: a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Fujiya
authors.affiliation: g Department of Surgery , Tohoku University Graduate School of Medicine , Sendai , Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: h Department of Neurosurgery , Miyagi Cancer Center , Natori , Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Katakura
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage; D011743:Pyrimidines
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: Anti-cancer fluoropyrimidine agent; FDA approval; dihydropyrimidine dehydrogenase inhibitor; fixed-dose combination drug; oral administration; prodrug