双嘧达莫的1期及药代动力学研究：一种核糖核苷酸还原酶抑制剂
A phase 1 and pharmacokinetic study of didox: a ribonucleotide reductase inhibitor.
作者信息
Veale D, Carmichael J, Cantwell B M, Elford H L, Blackie R, Kerr D J, Kaye S B, Harris A L
机构信息
Department of Respiratory Medicine, Freeman Hospital, Newcastle-upon-Tyne, UK.
出版信息
Br J Cancer. 1988 Jul;58(1):70-2. doi: 10.1038/bjc.1988.164.
Abstract
A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.
摘要
一项关于新型核糖核苷酸还原酶抑制剂迪多克斯（didox）的1期研究通过缓慢静脉注射递增剂量的该药物来进行。34例转移性癌无反应患者接受了该药物治疗。剂量从起始剂量192 mg/m²逐步递增至10 g/m²，共进行了13次剂量递增。在7.5 g/m²时出现了剂量限制性毒性，除了严重的胃肠道毒性外，还观察到肝肾功能紊乱。药代动力学研究表明，注射后5分钟内可达到迪多克斯的峰值水平。在1728 mg/m²时，数据最符合二室开放模型，平均血清α半衰期为5.2分钟，β半衰期为41.3分钟。不到10%的药物以原形经尿液排泄，且大部分排泄发生在6小时内。因此，迪多克斯以6 g/m²的剂量通过缓慢静脉注射给药是安全的。
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