L01BC02 - Fluorouracil |
Not porphyrinogenic |
NP |
Rationale
Non-CYP metabolism. Reported to be tolerated by 5 patients with AIP. Side effects such as nausea, vomiting and anorexia may be potentially porphyrinogenic through reduction in caloric intake.
Chemical description
Fluorouracil is an analogue of the pyrimidine uracil.
Therapeutic characteristics
Fluorouracil is used for the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The drug also is used as an adjunct to surgery for the treatment of various solid tumors (e.g., adenocarcinoma of the colon, rectal carcinoma, or breast cancer)Administered as as an intravenous injection or infusion. Common adverse reactions of fluorouracil that can be confused with an acute porphyric attack are nausea, vomiting, diarrhoes,and cerebral ataxia. Side effects such as nausea, vomiting and anorexia may be potentially porphyrinogenic through reduction in caloric intake.
Metabolism and pharmakokinetics
Fluorouracil is metabolized by dihydropyrimidine dehydrogenase, a non-CYP enzyme (Collins, J. M., 2000). Baumhakel et al (2001) states that fluorouracil has no inhibitory effect on CYP3A4. No observations pointing to clinical CYP-induction. Rendic (2002) reports fluorouracil to be a substrate for several smaller CYP-groups (1A2,2A6, 2C8, 2E1, 3A5), but not an inducer or inhibitor. In spite of reports of fluorouracil leading to increased effect of warfarin, Park et al found that fluorouracil has no inhibitory effect on CYP-isoforms or drug metabolism causing drug interaction
with fluorouracil, and concludes that the mechanism that causes drug interaction may not be related to direct CYP-inhibition by fluorouracil.
Published experience
Samuels et al (1984) reported unevenful use of 5-fluorouracil in 2 patients with VP. De Wet (1992) reported uneventtful use in a 56 year old woman with quiescent VP.
IPNet drug reports
Uneventful use reported twice in male VP patient, baseline PBG level was measured and then daily monitoring for a few days and then weekly until finished chemotherapy without any increase in PBG levels. Uneventful use reported in 62 year-old AIP female.
References
- Scientific articles
- Baumhakel, M., Kasel, D. et al. Screening for inhibitory effecs on antineoplastic agents on CYP3A4 in human liver microsomes. International Journal of Clinical Pharmacology and Therapeutics 2001; 39(12):517-28. #3337
- Park JY, Kim, KA. Inhibitory effect of 5-fluorouracil on human cytochrome P(450) isoforms in human liver microsomes. Eur J Clin Pharmacol 2003; 59:407â-9. PMID 12904931. #4571
- Rendic, S. Summary of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83-448. PMID 11996015. #4559
- Samuels, B., Bezwoda, W.R., et al. Chemotherapy in porphyria. S Afr Med J 1984; 65:924-6. #3341
- De Wet M, Jooste R. et al. Ondansetron in a patient with porphyria. S Afr Med J 1992; 82(6):480. #3338
- Drug reference publications
- McEvoy GK, editor. Fluorouracil. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (03.12.09). #3339
- Sweetman SC, editor. Martindale: The complete drug reference. Fluorouracil. Pharmaceutical Press 2009. #3342
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