Polak A, Eschenhof E, Fernex M, Scholer H J
Chemotherapy. 1976;22(3-4):137-53. doi: 10.1159/000221923.
Metabolism of 5-fluorocytosine-6-14C (5-FC) was studied in mice, rats, rabbits and dogs after oral and subcutaneous, single and repeated administration. In the urines of all species, intact 5-FC accounted for more than 90% of the total radioactivity at any time of the various treatment schedules. The average proportion of the urinary metabolites was around 5% in dogs, 3% in rabbits, 2.5% in rats, and 2% in mice of the total radioactivity. At repeated dosage, there was an increase of metabolites in mice but a decrease in rats treated subcutaneously. Neither increase nor decrease was observed in rabbits (treated orally) and dogs. Two metabolites were identified, alpha-fluoro-beta-ureido-propionic acid (FUPA) and alpha-fluoro-beta-alanine, the latter occurring mainly after oral treatment. These compounds represent probably that part of 5-FC which was deaminated to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil. FUPA was the only metabolite found in the urines collected from 4 out of 5 human volunteers during the first 12 h after single oral administration of 3.5 g of the radiolabelled drug. Its maximum proportion was 1.1% of the total radioactivity. No metabolites were detected in the urine neither of the 5th volunteer nor in those of 3 mycosis patients who were given the radioactive dose after they had received regular chemotherapy with unlabelled 5-FC (150 mg/kg/day) for at least 2 weeks. The sensitivity threshold of the method was 0.1-0.4% of the total radioactivity. One of the patients had developed thrombocytopenia which was probably due to 5-FC chemotherapy. The symptoms of 5-FC intolerance were in most of the examined species similar to those observed with 5-FU [9]. However, no quantitative correlation between proportion of metabolites and 5-FC toxicity is apparent except that man is the species in which both metabolism and toxicity are the lowest. It has not been proved yet that 5-FC intolerance occurring in a small percentage of patients receiving 5-FC chemotherapy (mainly leukopenia, thrombocytopenia) results in fact from conversion to 5-FU.
在小鼠、大鼠、兔子和狗身上，对5-氟胞嘧啶-6-¹⁴C（5-FC）经口服和皮下单次及重复给药后的代谢情况进行了研究。在所有物种的尿液中，在各种治疗方案的任何时间点，完整的5-FC在总放射性中所占比例均超过90%。尿中代谢物的平均比例在狗中约为5%，兔子中为3%，大鼠中为2.5%，小鼠中为2%（占总放射性）。重复给药时，小鼠体内代谢物增加，但皮下给药的大鼠体内代谢物减少。口服给药的兔子和狗体内未观察到增加或减少。鉴定出两种代谢物，α-氟-β-脲基丙酸（FUPA）和α-氟-β-丙氨酸，后者主要在口服给药后出现。这些化合物可能代表了5-FC中被脱氨为5-氟尿嘧啶（5-FU）或直接脱氨为5-氟二氢尿嘧啶的那部分。FUPA是在5名人类志愿者单次口服3.5 g放射性标记药物后的前12小时内，从其中4人的尿液中发现的唯一代谢物。其最大比例为总放射性的1.1%。在第5名志愿者的尿液中以及3名真菌病患者的尿液中均未检测到代谢物，这些患者在接受至少2周未标记的5-FC（150 mg/kg/天）常规化疗后接受了放射性剂量。该方法的灵敏度阈值为总放射性的0.1 - 0.4%。其中一名患者出现了血小板减少症，这可能是由于5-FC化疗所致。在大多数被检查的物种中，5-FC不耐受的症状与5-FU观察到的症状相似[9]。然而，除了人类是代谢和毒性都最低的物种外，代谢物比例与5-FC毒性之间没有明显的定量相关性。尚未证实接受5-FC化疗的一小部分患者（主要是白细胞减少症、血小板减少症）出现的5-FC不耐受实际上是由转化为5-FU引起的。
