title: 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.
authors.affiliation: AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK. roy.dsouza@astrazeneca.com
authors.forename: R A
authors.initials: RA
authors.lastname: D'Souza
authors.forename: E A
authors.initials: EA
authors.lastname: Partridge
authors.forename: D W
authors.initials: DW
authors.lastname: Roberts
authors.forename: S
authors.initials: S
authors.lastname: Ashton
authors.forename: A
authors.initials: A
authors.lastname: Ryan
authors.forename: A B
authors.initials: AB
authors.lastname: Patterson
authors.forename: Z
authors.initials: Z
authors.lastname: Wilson
authors.forename: C C
authors.initials: CC
authors.lastname: Thurrell
mesh_terms: D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D003078:Colchicine / Q000031:analogs & derivatives*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D050257:Tubulin Modulators; D003078:Colchicine