Rahman A, Smith F P, Luc P T, Woolley P V
Invest New Drugs. 1985;3(4):369-74. doi: 10.1007/BF00170760.
The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m2 over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7-10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2 alpha = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m2 would be acceptable for Phase II studies of this drug administered on this schedule.
已评估了作为24小时输注给药的谷氨酰胺拮抗剂6-重氮-5-氧代-L-正亮氨酸（DON）的毒性。还对3名患者进行了该药物的临床药理学研究。该药物的限制性毒性为急性恶心、呕吐和腹泻，其严重程度和持续时间呈剂量依赖性。最大耐受剂量为24小时内600mg/m²。另一个主要毒性是血小板减少，在输注完成后7-10天达到最大值。该药物未表现出肾、肝或中枢神经系统毒性。DON在这些输注过程中达到稳态水平，输注完成后按一级动力学消除（t1/2α = 1.81小时）。主要排泄途径是肾脏。对于按此方案给药的该药物的II期研究，起始剂量400mg/m²是可以接受的。
