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Expert Opin Drug Deliv. 2017 Dec;14(12):1355-1366. doi: 10.1080/17425247.2017.1316260. Epub 2017 Apr 11.

Drug delivery of oral anti-cancer fluoropyrimidine agents.

Author information

1
a Department of Surgery , Miyagi Cancer Center , Natori , Japan.
2
b Division of Cancer Chemotherapy , Miyagi Cancer Center Research Institute , Natori , Japan.
3
c Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Investigational Drug Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA.
4
d Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Regulatory Affairs Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA.
5
e Miyagi Cancer Center Research Institute , Division of Cancer Stem Cell , Natori , Japan.
6
f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan.
7
g Department of Surgery , Tohoku University Graduate School of Medicine , Sendai , Japan.
8
h Department of Neurosurgery , Miyagi Cancer Center , Natori , Japan.

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.

KEYWORDS:

Anti-cancer fluoropyrimidine agent; FDA approval; dihydropyrimidine dehydrogenase inhibitor; fixed-dose combination drug; oral administration; prodrug

PMID:
28379040
DOI:
10.1080/17425247.2017.1316260
[Indexed for MEDLINE]

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