Masurel D, Houghton P J, Young C L, Wainer I W
Department of Pharmacokinetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Cancer Res. 1990 Jan 15;50(2):252-5.
The enantiomers of the anticancer drug ifosfamide, (+)-(R)-IFF and (-)-(S)-IFF, were prepared from the racemic compound rac-IFF using enantioselective liquid chromatographic techniques. The efficacy, toxicity, and pharmacokinetics of the individual enantiomers and rac-IFF were studied in mice. The results of the studies indicate that there were no statistically significant differences between the efficacy of (+)-(R)-IFF, (-)-(S)-IFF, and rac-IFF against childhood rhabdomyosarcoma (HxRh28) maintained in vivo as a xenograft in immune-deprived female CBA/CaJ mice. Similar results were found in toxicity and pharmacokinetic studies conducted in non-tumor-bearing female CBA/CaJ mice. The production of two major metabolites, aldoifosfamide and isophosphoramide mustard, by mice hepatic microsomes from non-tumor-bearing female CBA/CaJ mice was also investigated. There were no statistically significant differences in the calculated kinetic parameters, Vmax and Km, of the production of these two metabolites when the separate enantiomers or the racemic mixture were used as substrate.
抗癌药物异环磷酰胺的对映体，即(+)-(R)-IFF和(-)-(S)-IFF，是采用对映体选择性液相色谱技术从外消旋化合物rac-IFF制备而来。对小鼠体内的单一异构体和rac-IFF的疗效、毒性及药代动力学进行了研究。研究结果表明，在免疫缺陷雌性CBA/CaJ小鼠体内作为异种移植瘤维持生长的儿童横纹肌肉瘤（HxRh28）模型中，(+)-(R)-IFF、(-)-(S)-IFF和rac-IFF的疗效之间无统计学显著差异。在无肿瘤雌性CBA/CaJ小鼠中进行的毒性和药代动力学研究也得到了类似结果。还研究了无肿瘤雌性CBA/CaJ小鼠的肝脏微粒体对两种主要代谢产物——醛异环磷酰胺和异环磷酰胺氮芥的生成情况。当分别使用对映体或外消旋混合物作为底物时，这两种代谢产物生成的计算动力学参数Vmax和Km无统计学显著差异。
