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Efficacy, Toxicity, Pharmacokinetics, and in Vitro Metabolism of the Enantiomers of Ifosfamide in Mice¹

Departments of Pharmacokinetics [D. M., C. L. Y., I. W. W.] and Biochemical and Clinical Pharmacology [P. J. H.], St. Jude Children's Research Hospital, Memphis, Tennessee 38105

The enantiomers of the anticancer drug ifosfamide, (+)-(R)-IFF and (-)-(S)-IFF, were prepared from the recemic 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, V_max and K_m, of the production of these two metabolites when the separate enantiomers or the racemic mixture were used as substrate.

¹ This work was supported by Grant CA23099 from the National Cancer Institute, by the Cancer Center Support (CORE) Grant CA21765, and by the American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed.

Received 5/ 8/89. Revised 9/27/89. Accepted 10/13/89.

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