Pharmacology of a new triazine antifolate in mice, rats, dogs, and monkeys.
Pharmacology of a new triazine antifolate in mice, rats, dogs, and monkeys.
复制标题
新型三嗪抗叶酸剂在小鼠、大鼠、狗和猴子中的药理学。
作者：
A. Cashmore;R. Skeel;D. R. Makulu;E. Gralla;J. Bertino
选择二氢叶酸还原酶的有效抑制剂三氮卓酮(TZT)进行详细研究，以确定其选择性作用机制及其在小鼠、大鼠、狗和猴子体内的代谢去向。TZT在正常小鼠和荷瘤小鼠的血清消失相似，有一个快速的组织平衡期和一个较慢的消除期。正常大鼠和荷瘤大鼠的血清消失时间为1.5~2.2小时。狗和猴子的血清消失率相似，半衰期分别为3~4小时和2~4小时。小鼠和大鼠24小时尿中TZT排泄量仅为注射剂量的5%~6%，而狗在8小时内排出注射剂量的60%。TZT在大鼠和小鼠的器官中蓄积程度相当，在肝、肾、脾和脑中的浓度逐渐降低。在给药后15分钟内，所有研究组织中的二氢叶酸还原酶活性几乎都检测不到。在荷瘤动物的腹水细胞中，药物积累的一个重要差异是：在小鼠中，L1210细胞中的药物水平始终低于腹水中的药物水平；相比之下，在TZT治疗30分钟后，Walker 256细胞中的药物水平是腹水中药物水平的10倍。无论是小鼠还是大鼠的尿液、粪便或器官组织的提取物中都没有发现药物代谢的证据。对TZT和两种相关的三嗪类药物静脉注射后在犬脑脊液中的蓄积能力进行了研究。行政管理。TZT的脑脊液水平在1小时时达到血清浓度的约15%；相反，其他两种三氮卓类药物在1小时时达到最大脑脊液水平的1%。
Triazinate (TZT), a potent inhibitor of dihydrofolate reductase, was selected for detailed investigation to determine its mechanism of selective action as well as its metabolic fate in mice, rats, dogs, and monkeys. The serum disappearance of TZT in normal and tumor-bearing mice was similar, with a rapid tissue equilibration phase and a slower elimination phase. Serum disappearance in normal and tumor-bearing rats was 1.5 to 2.2 hr. Serum disappearance in dogs and monkeys was similar, with half-lives of 3 to 4 and 2 to 4 hr, respectively. Urinary excretion of TZT at 24 hr was only 5 to 6% of the injected dose in mice and rats; in contrast, the dogs excreted 60% of the injected dose in 8 hr. TZT accumulated to comparable degrees in the organs of rats and mice, with progressively lesser concentrations in liver, kidney, spleen, and brain. Dihydrofolate reductase activity became almost undectectable in all tissues studied within 15 min after drug adminsitration. An important difference in drug accumulation was in the ascites cells of tumor-bearing animals: in mice, the drug level was consistently lower in the L1210 cells than in the ascites fluid; in contrast, by 30 min after treatment with TZT the drug level in Walker 256 cells was 10-fold higher than the level in the ascites fluid. No evidence for drug metabolism was found in extracts of urine, feces, or organ tissues from either mice or rats. TZT and two related triazines were studied for their ability to accumulate in the cerbrospinal fluid of dogs after i.v. administration. TZT achieved a cerebrospinal fluid level of approximately 15% of the serum concentration at 1 hr; in contrast, the other two triazines reached maximum cerebrospinal fluid values of 1% at 1 hr.