Distribution of radioactivity and metabolite profiling in tumour and plasma following intravenous administration of a colchicine derivative (14C-ZD6126) to tumour-bearing mice.

The main aim of the study was to investigate the distribution of radioactivity in the tissues and tumours using quantitative whole-body autoradiography (QWBA), together with a more detailed investigation of plasma and tumour samples, following administration of a single intravenous dose at 200 mg kg(-1) of 14C-ZD6126 to mice bearing subcutaneous Hras5 tumour xenografts. The study also included an assessment of tumour necrosis following administration of a single intravenous dose of non-labelled ZD6126 at 200 mgkg(-1). QWBA analysis showed that drug-related material was widely distributed to the tissues and tumour. In the majority of tissues, concentrations of radioactivity were highest at 15 min and declined rapidly thereafter. The tumour-to-plasma ratio was 0.6:1 at 0.25 h and increased to 6:1 at 48 h, indicating that drug-related material persisted in the tumour longer than in plasma. ZD6126, a phosphate ester, is rapidly hydrolysed to ZD6126 phenol, the active metabolite. The major metabolite in plasma (36% of the sample radioactivity) and all tumour samples (58-83% of the sample radioactivity) was confirmed as ZD6126 phenol. Extensive tumour necrosis was noted by 24h, which was still evident at 48 h, although there was some evidence of tumour regrowth.