Plasma levels of 5‐fluorouracil after oral and intravenous administration in cancer patients.

Finch, Rosemary E.; Bending, Michael R.; Lant, A. F.

doi:10.1111/j.1365-2125.1979.tb04651.x

Cited by 57 publications

(15 citation statements)

References 19 publications

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“…Christophidis et al (23) showed that oral administration of 5-FU (10-15 mg/kg) to 12 patients resulted in plasma drug levels that varied from 0 to 10.5 ug/ml and bioavailabilities that varied between 0 and 74%. Similar results were reported by others (24,25). Our studies showed that the oral administration of 5-FU to rats also produced large interanimal variability in 5-FU plasma concentration vs. time profiles (Fig.…”

Section: Resultssupporting

confidence: 80%

“…Disproportionate increases in AUC and half-life with increasing dose of i.v. 5-FU were observed in other clinical investigations (25,27). Our studies with 5-EU-treated rats (Fig.…”

Section: Resultssupporting

confidence: 55%

“…In contrast, 5-FU plasma profiles were considerably less variable after pretreatment with 5-EU (Fig. 1B) 25-fold increase in the amount ofuracil excreted into urine.…”

Section: Resultsmentioning

confidence: 85%

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5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil.

Baccanari

Davis

Knick

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

111

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5-Ethynyluracil (5-EU, 776C85) is a mechanism-based irreversible inhibitor of dihydropyrimidine dehydrogenase (EC 1.3.1.2), the rate-determining enzyme in 5-fluorouracil (5-FU) catabolism. In the present study, 5-EU was found to be a potent modulator of 5-FU catabolism in mice and rats. Liver extracts prepared up to 6 hr after a 5-EU dose (2 mg/kg) were >96% inhibited in their ability to catalyze 5-FU degradation. 5-EU treatment increased the elimination t1l2 and the area under the plasma concentration-time curve of 5-FU.5-FU oral bioavailability was "100% in rats pretreated with 5-EU. Consequently, 5-EU induced a linear relationship between the area under the plasma concentration-time curve and the oral dose of 5-FU. As expected from the preservation of plasma 5-FU, 5-EU potentiated the antitumor activity and the toxicity of 5-FU in two mouse tumor models (Colon 38 and MOPC-315). However, 5-EU potentiated the antitumor activity to a greater degree and thereby increased the therapeutic index of 5-FU 2-to 4-fold. was purchased from Moravek Biochemicals (Brea, CA). 5-FU and other reagents were purchased from Sigma.Cell Culture. MOPC-315 mouse myeloma tumor cells (American Type Culture Collection) were grown in RPMI 1640 medium (GIBCO/BRL) containing 2 mM L-glutamine and supplemented with 10o fetal bovine serum (HyClone) and 1 mM sodium pyruvate. Colon 38 carcinoma was obtained from the Development Therapeutics Program Tumor Repository (Frederick, MD).Animal Dosing and Sample Collection. Drugs were dissolved in alkaline saline (pH 8.5-10) and administered to mice in a volume of 10 ml/kg.

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Section: Resultssupporting

confidence: 80%

“…Disproportionate increases in AUC and half-life with increasing dose of i.v. 5-FU were observed in other clinical investigations (25,27). Our studies with 5-EU-treated rats (Fig.…”

Section: Resultssupporting

confidence: 55%

See 1 more Smart Citation

5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil.

Baccanari

Davis

Knick

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Plasma samples were analysed by gas liquid chromatography using a nitrogen detector as previously described (Finch et al, 1979). The maximum sensitivity of this assay was 1 ,ug/ml plasma.…”

Section: Assaymentioning

confidence: 99%

“…5FU may be administered either orally or parenterally. The bioavailability of the drug after oral administration varies considerably both between patients (28%-100%) (Cohen et al, 1974;Finn & Sadee, 1975;Murinson & Myers, 1978;Phillips et al, 1980) and within patients (Finch et al, 1979). Several factors may contribute to poor bioavailability.…”

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confidence: 99%

The influence of cimetidine on the pharmacokinetics of 5‐fluorouracil.

Harvey¹,

Slevin²,

Dilloway³

et al. 1984

Brit J Clinical Pharma

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1 The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. 2 Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. 3 Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 + 4.5 ,ug/ml (mean + s.e. mean) to 32.6 + 4.4 ,ug/ml (P < 0.05) and AUC was increased by 72% from 528 + 133 ,ug ml-' min (mean + s.e. mean) to 911 + 152 txg ml-' min (P < 0.05). After intravenous 5FU, AUC was increased by 27% from 977 + 96 ug ml-' min (mean + s.e. mean) to 1353 + 124 ,ug ml-' min (P < 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 ± 116 ml/min (mean + s.e. mean) to 711 ± 87 ml/min (P < 0.01). 4 The elimination half-life of 5FU was not altered by cimetidine. 5 The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.

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