Horváth I P, Csetényi J, Kerpel-Fronius S, Hegedüs L, Kanyár B, Eckhardt S
Eur J Cancer Clin Oncol. 1986 Feb;22(2):163-71. doi: 10.1016/0277-5379(86)90026-x.
Dianhydrogalactitol (DAG), labelled with 3H, was administered in single intravenous or oral doses to six patients (three in each group) with cancer. Kinetic parameters were calculated for the unchanged DAG and its biotransformation products. Elimination of the drug by metabolism and excretion was described by a catenary model. In order to elucidate the role of DAG as a mediator of the alkylating action of the cytostatic drug dibromodulcitol (DBD), the pharmacokinetic parameters of DAG and DBD were compared. The mean residence time for pharmacologically active molecules in the body was six times shorter for DAG (1.9 hr) than for DBD (11.4 hr). Alkylating action and metabolic degradation proceeded about 8-9 times faster for DAG than for DBD. The process of DBD alkylation implies a slow solvolytic conversion of the parent drug into the more reactive bromoepoxide and DAG. The preformed DAG would be rapidly consumed by intracellular alkylation and degradation, while unchanged DBD could form a depot in the cells and exert its cytostatic activity through the epoxides released in situ by solvolytic activation. Thus DBD entering the cells in unchanged form may have a more important role in its therapeutic effects than had been assumed earlier.
用³H标记的二脱水半乳糖醇（DAG）以单次静脉注射或口服剂量给予6例癌症患者（每组3例）。计算了未变化的DAG及其生物转化产物的动力学参数。药物通过代谢和排泄的消除情况用链状模型描述。为了阐明DAG作为细胞抑制药物二溴卫矛醇（DBD）烷基化作用介质的作用，比较了DAG和DBD的药代动力学参数。DAG（1.9小时）在体内药理活性分子的平均驻留时间比DBD（11.4小时）短6倍。DAG的烷基化作用和代谢降解比DBD快约8 - 9倍。DBD的烷基化过程意味着母体药物缓慢地溶剂解转化为反应性更强的溴代环氧化物和DAG。预先形成的DAG会通过细胞内烷基化和降解迅速消耗，而未变化的DBD可在细胞中形成储存库，并通过溶剂解活化原位释放的环氧化物发挥其细胞抑制活性。因此，以未变化形式进入细胞的DBD在其治疗效果中可能具有比先前假设更重要的作用。
