The Tris Formulation of Fluorouracil Is More Cardiotoxic Than the Sodium-Salt Formulations

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

“…The results of the present study along with those of two previous ones (Lemaire et al, 1992(Lemaire et al, , 1994 show that the cardiotoxicity of FU might have at least two origins. The first is the presence of fluorinated impurities in commercial solutions of FU derived from the degradation of FU in the basic medium required for its solubilization, which are metabolized into FHPA and FAC.…”

“…(Lemaire et al, 1992(Lemaire et al, , 1994 indicated that the cardiotoxicity of FU was due, at least in the isolated perfused rabbit heart model, to degradation compounds of this drug, namely fluoromalonic acid semi-aldehyde (FMASAld) and fluoroacetaldehyde (Facet). These are found in commercial solutions and are formed over time in the basic medium required to dissolve FU.…”

“…As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992(Lemaire et al, , 1994, is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.…”

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

“…The biochemical mechanism underlying these toxic side-effects remains unclear, although it has been postulated that 5-FU, and more precisely its main catabolite ex-fluoro-p-alanine (FBAL) (Mukherjee and Heidelberger, 1960;Bemadou et al, 1985;Heggie et al, 1987;Hull et al, 1988), might be transformed into fluoroacetate (FAC) (Koenig and Patel, 1970), a highly cardiotoxic and neurotoxic poison (Pattison and Peters, 1966). We demonstrated on the isolated perfused rabbit heart model that commercial solutions of 5-FU contain cardiotoxic impurities, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), that are derived from the degradation of 5-FU in the basic medium required for its solubilization and are metabolized into FAC and 2-fluoro-3-hydroxypropionic acid (FHPA), another cardiotoxic compound (Lemaire et al, 1992(Lemaire et al, , 1994. Moreover, we were the first to demonstrate experimentally the biotransformation of pure 5-FU into two new catabolites, FAC and FHPA, in the isolated perfused rat liver (IPRL) model and in rats (Arellano et al, 1994).…”

Interest of Fluorine-19 Nuclear Magnetic Resonance Spectroscopy in the Detection, Identification and Quantification of Metabolites of Anticancer and Antifungal Fluoropyrimidine Drugs in Human Biofluids

“…Nevertheless, it was demonstrated that pure FU or FBAL are slightly metabolized into FHPA and FAC in isolated perfused rat liver and in the rat in vivo [8] and that FHPA in human urine comes, at least partly, from FU metabolism [15] . FU for clinical use is dissolved at a 50 mg/ml concentration in sodium hydroxide solution (FU-NaOH) at pH ; 1.5 mol% were found in the FU-Tris formulations [7,16] . Since the FMASAld and Facet are found at very low concentrations in FU-NaOH vials (0.015 and 0.010% relative to nominal FU, respectively) but at much higher concentrations (1.0 and 0.3%, respectively) as oxazolidine adducts with Tris in FU-Tris solutions [7,16] .…”