摘要
应用体内１９ＦＮＭＲ谱观察并定量评价了５－氟尿嘧啶（５－ＦＵ）在荷Ｓ１８０瘤和Ｂ１６瘤小鼠肿瘤内的摄取和代谢动力学过程．５－ＦＵ２００ｍｇ·ｋｇ－１ｉｖ后，药物在Ｓ１８０和Ｂ１６瘤内的主要产物为其活性产物氟代核苷／核苷酸（ＦＮＵＣ），同时可检测到少量的降解产物α－氟－β－丙氨酸（ＦＢＡＬ）和α－氟－β－脲基丙酸（ＦＵＰＡ）．在Ｓ１８０瘤内，５－ＦＵ摄取，消除以及ＦＮＵＣ的生成有较大的个体变异，５－ＦＵ的消除半衰期ｔ１／２ｋｅ为４１．５－８４．８ｍｉｎ，ＦＮＵＣ生成ｔ１／２ｒ为２６．０－９１．９ｍｉｎ．当甲氨蝶呤（ＭＴＸ）与５－ＦＵ合用时，５－ＦＵ在Ｓ１８０瘤内的活化代谢过程明显加快，ｔ１／２ｋｅ缩短为２９．９－４３．４ｍｉｎ，ＦＮＵＣ的生成速率显著提高，生成量增加．５－ＦＵ在Ｂ１６瘤内的摄取及代谢过程的个体波动较小，其ｔ１／２ｋｅ为３９±５ｍｉｎ，ＦＮＵＣ的生成ｔ１／２ｒ为６０±７ｍｉｎ，在Ｂ１６瘤内，ＭＴＸ的合用不能明显加快５－ＦＵ转化为ＦＮＵＣ的反应，也不改变５－ＦＵ在瘤内的消除模式．上述结果表明，５－ＦＵ对肿瘤的化疗作用与肿瘤灌注５－ＦＵ在瘤组织内的摄取和活化代谢过程密切相关，亦可受到合用药物的影响．
The intratumoral uptake and metabolic kinetics of 5fluorouracil (5FU) were investigated and measured in S180 tumorbearing Kunming mice and B16 tumorbearing C57 mice by in vivo 19F nuclear magnetic resonance spectroscopy (19F NMR). The cytotoxic anabolites fluorinated nucleosides/tides (FNUC) were detected as the major metabolite both in S180 tumor and B16 tumor after iv 5FU 200 mg·kg-1. The degradation products, αfluoroβureidopropionic acid (FUPA) and αfluoroβalanine (FBAL) were minor metabolites, which appeared in 19F NMR spectra obtained from the tumors. The marked individual variation was shown in the uptake and clearance of 5FU, as well as the formation of FNUC in the S180 tumors. The range of elimination t1/2ke of 5FU was 41.5 to 84.8 min, and the formation t1/2r of FNUC was changed from 26.0 to 91.9 min in the S180 carcinosarcoma. Pretreatment with methotrexate (MTX) in S180 tumorbearing mice appeared to result in a significant enhancement of intratumoral anabolism of 5FU, and the elimination t1/2ke of 5FU was decreased to 29.9-43.4 min. Moreover, the production and formation rate of FNUC were increased significantly. In B16 tumors, the intratumoral uptake and elimination of 5FU (200 mg·kg-1, iv) were rapid. The t1/2ke of 5FU was 39±5 min, and the formation t1/2r of FNUC was 60±7 min. Pretreatment of MTX could not activated the intratumoral anabolic metabolism of 5FU, and not change the clearance profile of the drug in B16 tumors. These results demonstrate that the tumor toxicity of 5FU depends on tumor perfusion, uptake and anabolism of 5FU in the tumor tissue, and it can also be modulated by other drugs used concurrently.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
1998年第1期52-57,共6页
Chinese Journal of Pharmacology and Toxicology
关键词
氟尿嘧啶
抗肿瘤药
氟代核苷
氟19
核磁共振
5fluorouracil
fluorinated nucleosides/tides
methotrexate
pharmacokinetics
nuclear magnetic resonance
in vivo 19F
neoplasms
