In our study, the incidence of high-dose 5FU-CVI cardiotoxicity was 7.6%. The hypothesis of a toxic cardiomyopathic process requires further confirmation.

168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)

No abstract

-1 was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.

Summary The cardiotoxicity of 5-fluorouracil (FU) was attributed to impurities present in the injected vials. One of these impurities was identified as fluoroacetaldehyde which is metabolised by isolated perfused rabbit hearts into fluoroacetate (FAC), a highly cardiotoxic compound. FAC was also detected in the urine of patients treated with FU. These impurities were found to be degradation products of FU that . However, the precise biochemical mechanism underlying this toxic side-effect still remains unknown even if the metabolic pathways of FU have now been largely elucidated (Heidelberger et al., 1983). The cytotoxic activity of this drug stems from the anabolic pathway that leads to fluoronucleosides (FNUCs) then fluoronucleotides (FNUCt). The degradative pathway of FU biotransformation is called the catabolic pathway and mainly leads to a-fluoro-p-alanine (FBAL), an a-fluoro-13-amino-acid which closely resembles the natural P-amino-acid, 0-alanine. P-alanine is converted into acetate which enters the Krebs cycle and undergoes a metabolic conversion to citrate. By analogy with the natural substrate, it has been suggested but never demonstrated that FBAL might be transformed into fluoroacetate (FAC) (Philips et al., 1959;Koenig & Patel, 1970;Matsubara et al., 1980). FAC is known to be a highly cardiotoxic and neurotoxic poison. Indeed, it also enters the Krebs cycle, is then transformed into fluorocitrate (FC) which inhibits citrate metabolism resulting in accumulation of intracellular citrate (Pattison & Peters, 1966) (Figure 1).Having at our disposal a powerful method for studying the metabolism of fluorinated drugs, especially fluoropyrimidines (Malet-Martino et al., 1990), we explored the possibility of a direct toxic effect of FU or one of its metabolites on the mycocardium using fluorine-19 nuclear magnetic resonance ('9F NMR) and the isolated perfused rabbbit heart (IPRH) model. We also report in this paper the results of the '9F NMR analysis of biofluids from patients treated with FU. We demonstrate that a degradation compound of FU, resulting from the storage of this drug in alkaline conditions and found in the injected vials, is responsible for the cardiotoxicity of this antineoplastic drug since it is metabolised into FAC. Materials and methods MaterialsCommercial FU Roche vials from France (50 mg FU ml-' of an aqueous solution buffered with Tris, pH = 8.5), Germany (25 mg FU ml-' of an aqueous NaOH solution, pH = 8.5), Great Britain (25 mg FU ml-I of an aqueous NaOH solution, pH = 8.5), USA (50 mg FU ml-of an aqueous NaOH solution, pH = 9.2) and a commercial US generic from SoloPak Laboratories (50 mg FU ml-' of an aqueous NaOH solution, pH = 9