Fluorouracil toxicity

Leucovorin decreases the effectiveness of the anticonvulsants. There is an increased risk of 5-fluorouracil toxicity when the drug is administered with leucovorin. 

Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common phar-macogenetic syndrome. Cancer 1991 68 499-501. 

Wei X, McLeod HL, McMurrough J et al. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest 1996 98 610-615. 

Van Kuilenburg AB, Vreken P, Beex LV et al. Severe 5-fluorouracil toxicity caused by reduced dihydropyrimidine dehydrogenase activity due to heterozygosity for a G ->A point mutation. J Inherit Metab Dis 1998 21 280-284. 

Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity. Clin Cancer Res 1998 4 2999-3004. 

Bocci G, Danesi R, Allegrini G et al. Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil a case report. Eur J Clin Pharmacol 2002 58 593-595. 

Yokota H, Fernandez-Salguero P, Furuya H et al. cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria. J Biol Chem 1994 269 23192-23196. 

Garg MB, Sevester JC, Sakoff JA et al. Simple liquid chromatographic method for the determination of uracil and dihydrouracil plasma levels a potential pretreatment predictor of 5-fluorouracil toxicity. J Chromatogr B Analyt Technol Biomed Life Sci 2002 774 223-230. 

Sadoff L. Overwhelming 5-fluorouracil toxicity in patients whose diabetes is poorly controlled. Am J Clin Oncol 1998 21(6) 605-7. 

Valik D, Yeh KH, Cheng AL. Encephalopathy, lactic acidosis, hyperammonaemia and 5-fluorouracil toxicity. Br J Cancer 1998 77(10) 1710-2. 

A similar model was employed to predict the DDIs between 5-fluorouracil and sorivudine (124). Sorivudine is converted by gut flora to (E)-5-(2-bromovinyl) uracil, which inactivates dihydropyrimidine dehydrogenase and impairs the metabolism of 5-fluorouracil by this enzyme. This interaction led to 15 deaths in Japan from 5-fluorouracil toxicity due to elevated exposure to the drug. Using a fcE of 0.00018 min, a fivefold increase in the AUC of 5-fluorouracil was predicted after administration of sorivudine (150 mg/day for 5 days), which was close to the observed data in patients. 

Lynch HT, Droszcz CP, Albano WA, Lynch JF. Organic brain syndrome secondary to 5-fluorouracil toxicity. Dis Colon Rectum 1981 24(2) 130-1. 

Stein BN, Petrelh NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 1995 75(1) 11-17. 

Howell SB, Wung WE, Taetle R, Hussain F, Romine JS. Modulation of 5-fluorouracil toxicity... 

Tuchman M, Stoeckeler JS, Kiang DT et al. Familial pyrimidinemia and pyrimi-dinuria associated with severe fluorouracil toxicity. N Engl J Med 1985 313 245-249. 

Patients with poorly controlled diabetes are at risk of greater or more severe fluorouracil toxicity, causing hyperglycemia, which has been fatal. This effect seems to be independent of previous diabetic control and or fluorouracil dosage schedules (414)... 

FLUOROURACIL FOLIC ACID Risk of fluorouracil toxicity Folic acid exacerbates the inhibitory effect of fluorouracil on DNA Avoid co-administration... 

Does dihydropyrimidine dehydrogenase deficiency correlate with the occurrence of severe fluorouracil toxicity ... 

Cases of deliberate overdosage are unknown, but excessive duration or dosage of therapy will produce life-threatening toxicity because of the hematological effects and other symptoms and signs that are qualitatively similar to the adverse effects. There is no specific antidote to fluorouracil toxicity treatment consists of supportive care, including G-CSF and antidiarrheal agents. 

Barrett O Jr, Bourgeois C, Plecha FR. Fluorouracil toxicity following gastrointestinal surgery. Arch Surg 1965 91(6) 1002. ... 

FoxRM, WoodsRL, TattersallMHN, Piper AA, SampsonD. Allopurinol modulation of fluorouracil toxicity. Cancer Chemother Pharmacol (1981) 5, 151-5. 

A marked increase in fluorouracil toxicity was noted in 27 patients with metastatic colorectal cancer when they were given intravenous metronidazole 750 mg/m one hour before reeeiving intravenous fluorouracil 600 mg/m 5 days per week, every 4 weeks. Granuloeytopenia occurred in 74% of patients, nausea and vomiting in 48%, anaemia in 41%, stomatitis and oral ulceration in 34%, and thrombocytopenia in 19%. A pharmacokinetic study in 10 patients found that metronidazole reduced the clearance of fluorouracil by 27% over the 5-day period and increased the AUC by 34%. In vitro studies with human colon cancer cells failed to show any increased efficacy. ... 

Marked and rapidly fatal toxicity, attributed to fluorouracil toxicity, has been seen in patients given tegafur or other fluorouracil prodrugs with sorivudine. Fluorouracil is expected to interact similarly. 

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

Interest contmues in prodrugs of 5-fluorouracil (5-FU) Doxifluridine (8) was recently mtroduced and appears to be more potent and less toxic than 5 FU [10 Flutamide (9) and nilutamide (/O) are both available for the treatment of prostatic cancer [//, 12]... 

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