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

Abstract

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.

Dealing with PET radiometabolites

“…Several chromatographic techniques including thin-layer chromatography (TLC) [36], high-performance liquid chromatography (HPLC) [37], micellar chromatography [38], and overpressure thin-layer chromatography (OPTLC) [39] were commonly used for the examination of radiometabolites. Among these techniques, TLC was the earliest known chromatographic tool applied in radiochemistry to separate radioactive compounds.…”

Radiolabeled Absorption, Distribution, Metabolism, and Excretion Studies in Drug Development: Why, When, and How?

“…At the discovery stage, QWBA is a good tool for determining NME localization at the target site or to identify potential toxicological tissues. , D'Souza et al utilized QWBA in tumor-bearing mice to confirm that ZD6126 related drug components were evenly distributed in tissues and tumors and had a longer half-life in the tumor in comparison to plasma. In a rat QWBA study, an immunomodulator, fingolimod, developed for the treatment of relapsing multiple sclerosis disease, was found to be specifically localized along myelin sheaths, indicating a novel mechanism.…”

HPLC–NMR with severe column overloading: Fast-track metabolite identification in urine and bile samples from rat and dog treated with [14C]-ZD6126

“…It is a tumour-selective vascular targeting agent (VTA) which has shown activity in a wide range of preclinical tumour models, such as colorectal, lung, breast and prostate tumours grown as xenografts in nude mice [1,2,13]. Vascular targeting agents, such as ZD6126, disrupt the vascular network, crucial to the survival of and growth of solid tumours, by impairing blood vessel integrity, leading to vessel shut-down and consequently tumour necrosis [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. VTAs for the treatment of cancer are expected to show the greatest therapeutic benefit as part of combined modality regimens.…”