Studies on Fluorinated Pyrimidines XVI. Metabolism of 5-Fluorouracil-2-C14 and 5-Fluoro-2′-deoxyuridine-2-C14 in Cancer Patients
Studies on Fluorinated Pyrimidines XVI. Metabolism of 5-Fluorouracil-2-C14 and 5-Fluoro-2′-deoxyuridine-2-C14 in Cancer Patients
复制标题
癌症患者中 5-氟尿嘧啶-2-C14 和 5-氟-2-脱氧尿苷-2-C14 的氟化嘧啶代谢研究
作者：
K. Mukherjee;J. Boohar;D. Wentland;F. Ansfield;C. Heidelberger
摘要5-氟尿嘧啶-2-C14(FU)和5-氟-2‘-脱氧尿苷-2-C14(FUDR)分别通过口服、静脉、肌肉和腹膜途径给癌症患者。测定血浆、呼吸二氧化碳和尿液中的放射性，并用尿液和一些血浆酸溶提取物将离子交换柱上的放射性物质分离成不变的药物和各种降解产物。静脉注射FU-2-C14和FUDR-2-C14后前2小时的血浆放射性水平高于其他途径给药后。与口服、肌肉注射或腹膜注射相比，静脉注射后未改变的药物在尿液中持续的时间更长。静脉注射FUDR后，作为呼吸二氧化碳的放射性排泄最少。因此，静脉给药是临床应用这两种药物的首选方法。持续静脉注射的FU的降解率高于快速静脉注射的，而FUDR的降解率则相反。一名患者耐受大剂量的FUDR而没有毒性表现，药物迅速降解；而另一名患者迅速对FUDR产生毒性，其药物降解速度要慢得多。比较同一患者口服3‘，5’-二乙酰基-5-氟-2‘-脱氧鲁定-2-C14和FUDR-2-C14后24小时尿中5’-单乙酰基-FUDR的降解率，而FUDR后尿中未见不变药物。静脉注射FU-2-C14和FUDR-2-C14后，脑脊液中有放射性。放射性化合物的分级表明，脑脊液中存在未改变的药物。
Summary 5-Fluorouracil-2-C14 (FU) and 5-fluoro-2′-deoxyuridine-2-C14 (FUDR) were administered to cancer patients by oral, intravenous, intramuscular, and intraperitoneal routes. The radioactivity in the plasma, respiratory CO2, and urine was measured, and fractionation of radioactive materials on ion-exchange columns into the unchanged drug and the various degradation products was carried out with urines and some acid-soluble extracts of plasma. The level of radioactivity in the plasma was higher for the first 2 hours after intravenous injections of FU-2-C14 and FUDR-2-C14 than after administration by any other route. The unchanged drugs persisted longer in urine after intravenous injections than after oral, intramuscular, or intraperitoneal administrations. The excretion of radioactivity as respiratory CO2 was least after the intravenous injection of FUDR. It was concluded, therefore, that intravenous administration of both drugs is the method of choice in the clinical use of these drugs. There was more degradation of FU injected as a continuous infusion than following rapid intravenous injection, and the opposite was true for FUDR. One patient, who tolerated large doses of FUDR without toxic manifestations, degraded the drug rapidly; whereas a second patient, who rapidly became toxic to FUDR, degraded the drug at a much slower rate. When the degradation of 3′,5′-diacetyl-5-fluoro-2′-deoxyrudine-2-C14 and FUDR-2-C14, both given orally to the same patient, was compared, it was found that 5′-monoacetyl-FUDR was present in the urine 24 hours after administration of the diacetyl compound, whereas no unchanged drug was found in the urine after administration of FUDR. After intravenous injections of FU-2-C14 and FUDR-2-C14, radioactivity was found in the cerebrospinal fluid. Fractionation of the radioactive compounds demonstrated the presence of unchanged drug in the cerebrospinal fluid.