Clinical Pharmacology of 5-Fluorouracil

Abstract

5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

5-Fluorouracil sensitivity varies among oral micro-organisms

“…One of the main reasons for the short half-life time of 5-FU is the presence of dihydropyrimidine dehydrogenase (DPD) in humans which breaks down 80 % of the 5-FU to dihydrofluorouracil in the liver (Diasio & Harris, 1989). Patients with decreased DPD activity are more sensitive to 5-FU and are more likely to develop side effects, like mucositis, neurotoxicity and myelosuppression (Diasio et al, 1988;Harris et al, 1991;Takimoto et al, 1996).…”

Optimized permeation enhancer for topical delivery of 5-fluorouracil-loaded elastic liposome using Design Expert: part II

“…It is noteworthy that the tumor cells are exposed to the rate limiting-active metabolite for a short time locally within the tissue or systemically (10-20 min) when the 5-FU was administered with 600 mg/m 2 /day (Tanaka et al, 2000). Thus, oral administration of 5-FU has exhibited erratic and poor oral absorption, inter-and intrasubject variation and low plasma level leading to significant variation in BA indicating clinically limited therapeutic efficacy (Diasio & Harris, 1989). In addition, high and frequent dose administration of 5-FU to get improved oral BA is challenging and responsible for precipitating several serious side effects such as gastric disturbances and myelosuppression (Fraile et al, 1980;Lai & Guo, 2011).…”

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

“…Several enzymes involved in its metabolic activation eventually lead to the formation of active cytotoxic nucleotides or deoxynucleotides (Boyer et al, 2004). However, the major mechanism for 5-FU cytotoxicity is the formation of competitive 5-fluoro-2-deoxyuridine-5-monophosphate (FdUMP), thereby inhibiting TS activity with subsequent depletion of intracellular thymidine, suppression of DNA synthesis, and ultimately, apoptosis induction (Pinedo and Peters, 1988;Diasio and Harris, 1989;Langley et al, 2003). Overexpression of TS has been demonstrated to be associated with 5-FU resistance in patients with colorectal cancer (Johnston et al, 1995;Peters et al, 2002).…”