Kerpel-Fronius S, Erdélyi-Tóth V, Somfai-Relle S, Csetényi J, Kovács P, Ujj G, Kanyár B
National Institute of Oncology, Budapest, Hungary.
Cancer Chemother Pharmacol. 1988;22(2):109-13. doi: 10.1007/BF00257306.
The pharmacokinetics of diacetyldianhydrogalactitol (DADAG) was compared in mice, rats, and humans. The ratios of human therapeutic dose (ThD) to the LD10 were 8 and 5 in mice and rats, respectively. The ratios of the corresponding AUCs of DADAG were 20 and 17, whereas those of dianhydrogalactitol (DAG), the main, active metabolite of DADAG, were 8 in both species. The lower human-to-rodent ratio for DAG was due to the fact that twice as much DAG was formed in the animals. Other factors contributing to the larger AUC in man were the 3-5 times smaller distribution volume found in humans as well as the lower hexitol sensitivity of human bone marrow cells. We conclude that in addition to the distance between the AUCs of the LD10 and of the human starting dose, interspecies pharmacokinetic differences should also be considered in planning the rate of dose escalation.
对双乙酰去水半乳糖醇（DADAG）在小鼠、大鼠和人类中的药代动力学进行了比较。在小鼠和大鼠中，人类治疗剂量（ThD）与LD10的比值分别为8和5。DADAG相应的AUC比值分别为20和17，而DADAG的主要活性代谢产物去水半乳糖醇（DAG）在这两个物种中的比值均为8。人类与啮齿动物DAG比值较低是因为动物体内形成的DAG是人类的两倍。导致人类AUC较大的其他因素包括人类分布容积小3 - 5倍以及人类骨髓细胞对己糖醇的敏感性较低。我们得出结论，在规划剂量递增速率时，除了LD10和人类起始剂量的AUC之间的差距外，还应考虑种间药代动力学差异。
