Lelieveld P, van der Vijgh W J, van Velzen D
Eur J Cancer Clin Oncol. 1986 Dec;22(12):1467-73. doi: 10.1016/0277-5379(86)90081-7.
Preclinical studies on toxicology and pharmacokinetics were performed for (1,1-bis(aminomethyl)cyclohexane)oxalatoplatinum(II) (TNO-38) in rats and a dog after LD10 and LD50 assessment in mice. In drug-treated rats, ura and creatinine concentrations were 1.4-1.9 times those in control rats. Histopathology showed necrosis of tubular epithelium of the kidneys, which was comparable to damage observed after treatment with cisplatin (CDDP), and extensive necrosis of crypt epithelium, especially in the ileum. Similar to CDDP, TNO-38 was emetic in the dog. Non-specific subacute inflammatory changes were observed in the ileum. Renal damage was much less pronounced. Half-lives of distribution and elimination were 6.2 min and 5.2 days, respectively. The cumulative excretion of Pt in urine over 1 and 7 days after drug treatment was 38.3 and 49.3% of the dose, respectively. Twelve weeks after drug administration, Pt concentrations were highest in kidneys and liver. TNO-38 is adequately water soluble. Its reported antitumour activity is consistently lower than that of CDDP. The drug's toxicity was, in general, comparable to that of CDDP. Its pharmacokinetic profile was very similar to that of CDDP. It is concluded that TNO-38 should probably not be further evaluated in clinical studies.
在对小鼠进行LD10和LD50评估后，对大鼠和犬进行了(1,1 - 双(氨甲基)环己烷)草酸铂(II)(TNO - 38)的毒理学和药代动力学临床前研究。在药物治疗的大鼠中，尿素和肌酐浓度是对照大鼠的1.4 - 1.9倍。组织病理学显示肾脏肾小管上皮坏死，这与顺铂(CDDP)治疗后观察到的损伤相当，并且隐窝上皮广泛坏死，尤其是在回肠。与CDDP相似，TNO - 38在犬中会引起呕吐。在回肠观察到非特异性亚急性炎症变化。肾脏损伤不太明显。分布半衰期和消除半衰期分别为6.2分钟和5.2天。药物治疗后1天和7天尿液中铂的累积排泄量分别为给药剂量的38.3%和49.3%。给药12周后，铂浓度在肾脏和肝脏中最高。TNO - 38具有足够的水溶性。其报道的抗肿瘤活性始终低于CDDP。该药物的毒性总体上与CDDP相当。其药代动力学特征与CDDP非常相似。结论是TNO - 38可能不应在临床研究中进一步评估。
