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Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors
- Source :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 18(23)
- Publication Year :
- 2000
-
Abstract
- PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m2 on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m2 PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m2 PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m2 PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU–eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m2 PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.
- Subjects :
- Adult
Male
Cancer Research
medicine.medical_specialty
Antimetabolites, Antineoplastic
medicine.medical_treatment
Leucovorin
Administration, Oral
Neutropenia
Pharmacology
Gastroenterology
Drug Administration Schedule
Pharmacokinetics
Oral administration
Internal medicine
Neoplasms
Antineoplastic Combined Chemotherapy Protocols
medicine
Dihydropyrimidine dehydrogenase
Humans
Enzyme Inhibitors
Infusions, Intravenous
Uracil
Dihydrouracil Dehydrogenase (NADP)
Aged
Chemotherapy
business.industry
Middle Aged
medicine.disease
Regimen
Oncology
Fluorouracil
Toxicity
Female
business
Oxidoreductases
medicine.drug
Subjects
Details
- ISSN :
- 0732183X
- Volume :
- 18
- Issue :
- 23
- Database :
- OpenAIRE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....491fc9cd2dc160077f6cdf2dd19ce5b3