The absorption, distribution, excretion, and biotransformation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in animals.
The absorption, distribution, excretion, and biotransformation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in animals.
复制标题
抗癌剂 1-(2-氯乙基)-3-环己基-1-亚硝基脲在动物体内的吸收、分布、排泄和生物转化。
作者：
V. Oliverio;W. M. Vietzke;M. K. Williams;R. Adamson
在小鼠、大鼠、犬和猴中研究了1-（2-氯乙基）-3-环己基-1-亚硝基脲（一种抗腹腔内和颅内小鼠白血病L1210的高活性药物）的生理处置，分子的3个位置（乙烯、羰基和环己基部分）均带有14 C标记。1-（2-氯乙基）-3-环己基-1-亚硝基脲是脂溶性的，胃肠外给药后，在小鼠和犬血浆中迅速降解，有2个指数期。初始阶段的半衰期约为5分钟，而第二阶段延长超过1小时。在6小时后，静脉注射乙烯标记的1-（2-氯乙基）-3-环己基-1-亚硝基脲在狗，脑脊液中的放射性超过血浆的3倍。在环己基部分标记时，血浆放射性约为脑脊液14 C水平的50%。生物转化后的药物主要通过肾脏排泄，啮齿动物和猴在前24小时内基本完成排泄，但在犬中排泄时间更长。胆汁分泌和胃肠道重吸收已得到证实。分子的环己基部分广泛结合（40至60%），而乙烯部分不与犬的血浆蛋白结合。在小鼠中，胃肠外或口服给药后1天，在呼出的CO2中回收了10%至20%的羰基和4%至6%的乙烯碳原子。环己胺、N，N′-二环己基脲等主要未鉴定分子的检出支持亚硝基脲在体内降解过程中形成中间体羟基重氮烷和异氰酸酯的假设。然而，发现所鉴定的催化剂和环己基异氰酸酯对小鼠白血病L1210无活性。
Summary The physiological disposition of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, a highly active agent against intraperitoneal and intracranial mouse leukemia L1210, was studied in mice, rats, dogs, and monkeys with the 14C label in each of 3 positions of the molecule, the ethylene, carbonyl, and cyclohexyl moieties. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea is lipid soluble and, after parenteral dosage, rapidly degraded in mouse and dog plasma with 2 exponential phases. The half-life of the initial phase is about 5 min, while the 2nd phase extends over 1 hr. During the 6 hr after i.v. injection of ethylene-labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in dogs, radioactivity in the cerebrospinal fluid exceeded that of plasma 3-fold. With the label in the cyclohexyl moiety, plasma radioactivity was about 50% of cerebrospinal fluid 14C levels. The drug following biotransformation is primarily excreted by the kidneys with excretion being essentially complete during the first 24 hr in rodents and monkeys, but more protracted in dogs. Biliary secretion and reabsorption from the gastrointestinal tract have been demonstrated. The cyclohexyl portion of the molecule was bound extensively (40 to 60%), while the ethylene moiety was not bound to plasma proteins of dogs. In mice, 10 to 20% of the carbonyl and 4 to 6% of ethylene carbon atoms were recovered in expired CO2 1 day after parenteral or oral dosage. The detection of cyclohexylamine, N, N′-dicyclohexylurea, among other predominant unidentified molecular species, supports the hypothesis of intermediate hydroxydiazoalkane and isocyanate formation during the degradation of nitrosoureas in vivo. However, the identified catabolites and cyclohexyl isocyanate were found to be inactive against the mouse leukemia L1210.