| BACKGROUND: Glufosfamide, β-D-Glucopyranosyl-[N, N-bis[(2-chloroethyl)] phosphoric acid diamide, is a new alkylating agent. It contains an active alkylating moiety (isophosphoramide mustard) linked to β-D-glucose. Cellular uptake of glufosfamide is mediated by a Na~+-dependent β-D-glucose trans-membrane transporter (SAAT1) that is followed by intracellular enzymatic cleavage of the O-glysocidic bond and release of isophosphoramide mustard (IPM). This targeting mechanism, together with the accelerated metabolic rate and increased glucose consumption of tumor cells, suggests potentially enhanced tumor selectivity for glufosfamide and introduces a novel concept for drug targeting. Glufosfamide was generally well tolerated and showed anti-tumour activity against breast, colon, non-small cell lung and pancreatic cancers. In the present, glufofamide was under the phase of preclinical study.OBJECTIVES: The objectives of this study were to elucidate the pharmacokinetics and distribution profiles of glufosfamide in animals (rats and dogs), to investigate the differences in distribution between in normal nude mice and in nude mice with tumor, and to investigate the effect of glufosfamide on the major isoenzymes of CYP450 in rat microsome. The further objective was to predict the process of glufosfamide in human exactly and to estimate its effectiveness and toxicity reasonably.METHODS: The stability of glufosfamide in buffer solution with different pH and temperatures, and in biological samples was investigated using a liquid chromatography-iontrap mass spectrometric (LC/MS~n) method. The main factor for the degradation of glufosfamide in biological samples was investigated by the means of enzyme dynamic experiment for β-glucosidase and enzyme hydrolysis and inhibition experiments for β-glucuronidase. A sensitive and selective high-performance liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed for... |
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