Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche)

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study

“…Other mechanisms have been proposed, including direct toxicity on the myocardium (Levillain 1972;Matsubara et al 1980), activation of autoimmune responses (Stevenson et al 1977) or the production of Xuoro-acetaldehyde, generated in the alkaline solution of 5FU vials during storage, which is converted in vivo to the cardiotoxic Xuoro-acetate (Lemaire et al 1991). Recent experimental evidence supports a direct toxic eVect of 5FU on the coronary endothelial intima (Cwikiel et al 1996a(Cwikiel et al , 1995(Cwikiel et al , 1996b.…”

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

“…They are 2-fluoro-3-hydroxypropanoic acid (FHPA) and FAC [35,59]. As FU commercial formulations are not pure, FAC and FHPA arise from both the metabolism of impurities and that of FU itself [35,59]. Hull et al [40] also detected FHPA in urine of patients treated with FU but did not identify this compound.…”

“…Low levels of two compounds that are fluorinated analogues of ␤-alanine metabolites are detected with 19 F NMR in urine of patients treated with FU. They are 2-fluoro-3-hydroxypropanoic acid (FHPA) and FAC [35,59]. As FU commercial formulations are not pure, FAC and FHPA arise from both the metabolism of impurities and that of FU itself [35,59].…”

In Reply:

“…Several cases of severe, yet generally reversible, global left ventricular failure have been reported. [7][8][9] Between March 2002 and September 2002, we observed one case of lethal hyperammoniemic encephalopathy and two cases of severe, reversible left ventricular failure in patients receiving high-dose continuous FU. The mechanism of cardiotoxicity and neurotoxicity is not fully understood.…”

“…1,2 The presentation of these toxicities is variable. 5, 6 Lemaire et al 7,8 and Arellano et al 9 postulated that two degradation products in commercially available FU preparations, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), may be responsible, at least partly, for cardiotoxicity because these two compounds are highly cardiotoxic on the isolated perfused rabbit heart model, and Facet is also transformed to FAC in vivo. 3 Yeh and Cheng 4 observed a 5.7% incidence of FU-induced encephalopathy associated with hyperammonemia and lactic acidosis in patients receiving high-dose continuous FU.…”