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Figure 3. Tumour Concentration of H Paclitaxel Following CT-2103 or Taxol

The exposure of B16 melanoma tumours to TTAX was greatly enhanced following PG-[3H]TXL treatment when compared with [3H]TXL, the former yielding 170% higher Cmax and 1,100% higher AUC (Table 2, Figure 3). The overall exposure as indicated by AUC to ETAX and TXL was higher, 97% and 32% respectively, following PG-[3H]TXL administration. Mean residence times were 122%, 232%, and 288% higher, for TTAX, ETAX, and TXL, respectively, for the PG-[3H]TXL group and correlated with the observed increases in AUC 15. Although conjugated paclitaxel is inert, it can be assumed that slow breakdown of the remaining conjugate continued after the experiment was terminated at 144 hours. Paclitaxel-2'-y-glutamic acid ester was identified as a metabolite in tumour, liver and spleen, but not plasma, in the PG-[3H]TXL treated animals. This abundant metabolite is formed during proteolysis of the polyglutamate backbone, the apparent initial step in CT-2103 metabolism by both tumour and reticuloendothelial tissues.

These study results indicate that distribution of CT-2103 to tumour tissue and tumour exposure to TXL were enhanced compared with TXL administered alone, and provide at least a partial explanation for enhanced efficacy of CT-2103 compared to free paclitaxel15.

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